76
SmI 2 H 2 O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades Irem Yalavac, Sarah E. Lyons, Michael R. Webb, and David J. Procter †* School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK [email protected] Supplementary Information General Methods ...................................................................................................................... 2 Experimental Protocols and Characterisation Data ............................................................. 3 Crystal data and Structure Refinements ............................................................................. 41 Figure S1 Crystal Structure of 2b (CCDC 1009956) ............................................... 41 Table S1 Crystal data and structure refinement for 2b (CCDC 1009956) ............ 41 Figure S2 Crystal Structure of 2d (CCDC 1012766) ............................................... 43 Table S2 Crystal data and structure refinement for 2d (CCDC 1012766) ............ 43 References ............................................................................................................................... 45 1 H and 13 C NMR spectra ....................................................................................................... 46 Corresponding Author: Professor David J. Procter School of Chemistry, University of Manchester Oxford Road Manchester, M13 9PL, United Kingdom Electronic Supplementary Material (ESI) for ChemComm. This journal is © The Royal Society of Chemistry 2014

SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

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Page 1: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-Mediated 5-exo/6-exo Lactone

Radical Cyclisation Cascades

Irem Yalavac,† Sarah E. Lyons,

† Michael R. Webb,

‡ and David J. Procter

†*

†School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

‡Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1

2NY, UK

[email protected]

Supplementary Information

General Methods ...................................................................................................................... 2

Experimental Protocols and Characterisation Data ............................................................. 3

Crystal data and Structure Refinements ............................................................................. 41

Figure S1 Crystal Structure of 2b (CCDC 1009956) ............................................... 41

Table S1 Crystal data and structure refinement for 2b (CCDC 1009956) ............ 41

Figure S2 Crystal Structure of 2d (CCDC 1012766) ............................................... 43

Table S2 Crystal data and structure refinement for 2d (CCDC 1012766) ............ 43

References ............................................................................................................................... 45

1H and

13C NMR spectra ....................................................................................................... 46

Corresponding Author:

Professor David J. Procter

School of Chemistry, University of Manchester

Oxford Road

Manchester, M13 9PL, United Kingdom

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2014

Page 2: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S2

General Methods

1H-NMR and

13C-NMR spectra were recorded on Bruker NMR spectrometers (400 MHz and

500 MHz for 1H-NMR, 100 MHz and 125 MHz for

13C-NMR).

1H-NMR chemical shifts (δH)

and 13

C-NMR chemical shifts (δC) are quoted in parts per million (ppm) downfield from

trimethylsilane (TMS) and coupling constants (J) are quoted in Hertz (Hz). Abbreveations

for NMR data are s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sxt (sextet).

Infrared (IR) spectra were recorded on a Bruker Alpha FTIR spectrometer and mass spectra

were recorded on a Micromass Platform II (ESI), Agilent 5975C Triple Axis GCMS (GC-

MS, EI/CI) and Waters QTOF (HRMS). 1H-NMR and

13C-NMR spectra were assigned with

the aid of COSY, HSQC, HMBC and DEPT 90/135 NMR techniques and stereochemistry

assigned with the aid of X-ray crystallography. Flash column chromatography was carried

out using Sigma Aldrich silica gel 60 Angstrom (Ǻ), 240 – 400 mesh. Thin layer

chromatography (TLC) was performed on aluminium sheets pre-coated with silica gel, 0.20

mm (Macherey-Nagel, Polygram® Sil G/UV254). TLC plates were visualised by UV

absorption, phosphomolybdic acid, vanillin or potassium permanganate solution and heating.

Diiodoethane was washed with diethyl ether and sodium thiosulfate before use.

Tetrahydrofuran (THF) was pre-dried over sodium wire and distilled from sodium

benzophenone ketyl prior to use. Diisopropylamine (DIPA) and dichloromethane (DCM)

were both distilled from calcium hydride prior to use.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S3

Experimental Protocols and Characterisation Data

Preparation of SmI21

An oven-dried flask equipped with a dry stirrer bar was flushed with a strong flow of N2 for

30 minutes and loaded with samarium metal (-40 mesh, 1.4 equiv.) and washed diiodoethane

(1 equiv.). The flask was flushed for another 30 minutes, after which freshly distilled and

degassed THF (0.1 M) was added under stirring. Using an exit needle and a gentle flow of N2

for the first 5-10 minutes allowed for any ethene gas formed in-situ to evacuate the reaction

vessel. Stirring was continued under a positive pressure of N2 overnight at room temperature.

Before titration, the mixture was allowed to settle for one hour and used straight away.

Ethyl 4-(2-methyl-1,3-dioxolan-2-yl)butanoate – S12

To a stirred solution of ethyl 5-oxohexanoate (2.00 mL, 12.6 mmol, 1 equiv.) and ethylene

glycol (2.50 mL, 44.3 mmol, 3.5 equiv.) in benzene (18 mL) was added p-toluenesulfonic

acid monohydrate (48.0 mg, 0.25 mmol, 0.02 equiv.) and the mixture was heated to reflux for

21 hours using Dean-Stark conditions. The solvent was removed in vacuo and purification by

flash column chromatography (5% EtOAc:hexane) yielded the named compound as a

colourless oil (1.95 g, 77%); δH (400 MHz, CDCl3) 1.26 (3H, t, J 7.1, CO2CH2CH3), 1.33

(3H, s, CH3), 1.61 – 1.79 (4H, m, 2 × CH2), 2.33 (2H, t, J 7.1, CH2), 3.89 – 3.99 (4H, m, 2 ×

OCH2), 4.13 (2H, q, J 7.2, CO2CH2CH3); δC (100 MHz, CDCl3) 14.2 (CH2CH3), 19.6 (CH2),

23.8 (CH3), 34.3 (CH2), 38.3 (CH2), 60.2 (CH2CH3), 64.6 (-OCH2CH2O-), 109.8 (C-

OCH2CH2O-), 173.5 (CO2Et).

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S4

General Procedure A: Alkylation of protected keto-esters

Ethyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)hept-6-enoate – S2

An oven-dried flask was degassed with N2 and n-BuLi (5.00 mL, 7.89 mmol, 1.1 equiv., 1.6

M in hexane) was added slowly to a mixture of DIPA (1.10 mL, 7.89 mmol, 1.1 equiv.) and

THF (4.5 mL) at -78 °C. After stirring the solution for 1 hour at -78 °C, ethyl 4-(2-methyl-

1,3-dioxolan-2-yl)butanoate (1.45 g, 7.17 mmol, 1 equiv.) in THF (2.8 mL) was added over

30 minutes using a syringe pump. Stirring was continued for 45 minutes and 5-bromo-1-

pentene (1.15 mL, 9.75 mmol, 1.36 equiv.) in HMPA (1.5 mL) was added to the mixture,

which was allowed to warm to room temperature and stirred overnight. The reaction was

quenched with an aqueous saturated solution of NH4Cl (20 mL). After separation, the

aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layers were combined and

washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. Flash column

chromatography (5% EtOAc:hexane) yielded the named compound as a yellow oil (1.20 g,

62%); υmax / cm-1

3078, 2978, 2934, 2862, 1718, 1641, 1446, 1367, 1156, 1027, 911; δH (400

MHz, CDCl3) 1.22 (3H, t, J 7.6, CO2CH2CH3), 1.26 (3H, s, CH3), 1.31 – 1.38 (2H, m, CH2),

1.39 – 1.71 (6H, m, 3 × CH2), 1.97 – 2.05 (2H, m, C=CHCH2), 2.24 – 2.33 (1H, m, CH), 3.83

– 3.93 (4H, m, 2 × OCH2), 4.1 (2H, qd, J 7.3, 1.3, CO2CH2CH3), 4.87 – 5.00 (2H, m,

C=CHCH2), 5.67 – 5.79 (1H, m, C=CHCH2); δC (100 MHz, CDCl3) 14.2 (CH2CH3), 23.6

(CH3), 26.5 (CH2), 26.6 (CH2), 31.7 (CH2), 33.5 (CH2), 36.5 (CH2), 45.3 (CH), 60.0

(CH2CH3), 64.5 (-OCH2CH2O-), 64.5 (-OCH2CH2O-), 109.6 (C-OCH2CH2O-), 114.6

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S5

(CH=CH2), 138.3 (CH=CH2), 175.9 (CO2Et); m/z (ESI+) 294 ([M + Na]+, 100%); HRMS

(ESI+) found 271.1898, expect 271.1904 for C15H27O4.

General Procedure B: Deprotection of alkylated keto-esters

Ethyl 2-(3-oxobutyl)hept-6-enoate – S3

A mixture of ethyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)hept-6-enoate (0.60 g, 2.22 mmol,

1 equiv.), p-toluenesulfonic acid monohydrate (0.84 g, 4.44 mmol, 2 equiv.) and acetone (25

mL) was stirred at room temperature for 2 hours. After quenching with an aqueous saturated

solution of NaHCO3 (20 mL), the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The

organic layers were combined and dried over Na2SO4 and the crude compound was

concentrated in vacuo. The title compound was obtained by flash column chromatography

(5% EtOAc:hexane) as a colourless oil (0.48 g, 96%); υmax / cm-1

2935, 1720, 1367, 1158; δH

(400 MHz, CDCl3) 1.26 (3H, t, J 7.2, CO2CH2CH3), 1.33 – 1.52 (3H, m, 1H from CH2 +

CH2), 1.58 – 1.69 (1H, m, 1H from CH2), 1.81 (2H, q, J 7.5, CH2), 2.05 (2H, q, J 6.8,

C=CHCH2), 2.13 (3H, s, CH3), 2.29 – 2.38 (1H, m, CH), 2.44 (2H, td, J 7.6, 3.0, COCH2),

4.14 (2H, q, J 6.8, CO2CH2CH3), 4.92 – 5.04 (2H, m, HC=CH2), 5.71 – 5.84 (1H, m,

HC=CH2); δC (100 MHz, CDCl3) 14.3 (CH2CH3), 25.9 (CH2), 26.5 (CH2), 30.0 (CH2), 31.8

(CH3), 33.5 (CH2), 41.1 (CH2), 44.6 (CH), 60.3 (CH2CH3), 114.7 (CH=CH2), 138.3

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S6

(CH=CH2), 175.7 (CO2Et), 208.0 (CO); m/z (ESI+) 249 ([M + Na]+, 100%); HRMS (ESI+)

found 249.1450, expect 249.1461 for C13H22O3Na.

General Procedure C: Appel reaction

(3-Bromoprop-1-yn-1-yl)benzene – S42

To a stirred mixture of 3-phenyl-2-propyn-1-ol (1.00 g, 7.57 mmol, 1 equiv.) in CH2Cl2 (25

mL) was added CBr4 (3.01 g, 9.09 mmol, 1.2 equiv.) and the mixture was cooled to 0 °C.

PPh3 (2.38 g, 9.09 mmol, 1.2 equiv.) was added in 3 portions and the reaction was stirred

under N2 at room temperature for 3 hours. The solvent was removed in vacuo and inorganic

residues were removed by filtration through silica gel (hexane → 1% EtOAc:hexane). The

crude product was taken through to the next step; δH (500 MHz, CDCl3) 4.18 (2H, s, CH2Br),

7.3 – 7.4 (3H, m, ArCH), 7.42 – 7.52 (2H, m, ArCH); δC (125 MHz, CDCl3) 15.3 (CH2), 84.2

(C≡C), 86.7 (C≡C), 122.1 (ArC), 128.3 (ArCH), 128.9 (ArCH), 131.9 (ArCH).

Page 7: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S7

General Procedure D: Barbier-type lactonization reaction

rac-(3R,6S)-6-Methyl-3-(pent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-yl)tetrahydro-2H-

pyran-2-one – trans-1a and rac-(3S,6S)-6-ethyl-3-(pent-4-en-1-yl)-6-(1-phenylpropa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – cis-1a

An oven-dried flask was degassed with N2 and loaded with NiI2 (8 mg, 0.027 mmol, 2 mol%

with respect to SmI2) and SmI2 (17.0 mL, 1.33 mmol, 3 equiv.) and the mixture was cooled to

0 °C. Immediately after the addition of ethyl 2-(3-oxobutyl)hept-6-enoate (100 mg, 0.44

mmol, 1 equiv.) to the stirring mixture, (3-bromoprop-1-yn-1-yl)benzene (112 mg, 0.57

mmol, 1.3 equiv.) in THF (4.4 mL) was added dropwise over 30 minutes. Once warmed up to

room temperature, the reaction was opened to air and stirred until decolourisation occurred.

The reaction was quenched with Rochelle’s salt (10 mL) and extracted from Et2O (3 × 15

mL). The organic layers were washed with brine (20 mL) and dried over Na2SO4. The solvent

was removed in vacuo and flash column chromatography (5% EtOAc:hexane) yielded trans-

1a and cis-1a as a yellow oil (28 mg, 21% each, combined yield 42%).

For trans-1a: υmax / cm-1

3075, 2931, 2860, 1773, 1728, 1445, 1216, 1073, 907, 853, 765, 700;

δH (400 MHz, CDCl3) 1.42 - 1.54 (3H, m, 1H from CH2 + CH2), 1.61 (3H, s, CH3), 1.62 -

1.69 (1H, m, 1H from CH2), 1.83 - 1.87 (1H, m, 1H from CH2), 1.88 - 1.96 (1H, m, 1H from

CH2), 2.04 - 2.15 (3H, m, 1H from CH2 + CH2), 2.23 (1H, ddd, J 14.1, 7.6, 6.3, 1H from

CH2), 2.38 - 2.45 (1H, m, CH), 4.93 - 5.06 (2H, m, HC=CH2), 5.11 (2H, s, C=CH2), 5.80

(1H, ddt, J 17.1, 10.2, 6.7, HC=CH2), 7.25 - 7.29 (1H, m, ArH), 7.30 - 7.37 (2H, m, ArH),

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S8

7.41 - 7.47 (2H, m, ArH); δC (100 MHz, CDCl3) 22.6 (CH2), 26.1 (CH2), 28.1 (CH3), 30.9

(CH2), 31.8 (CH2), 33.6 (CH2), 38.6 (CH), 78.6 (C=CH2), 82.9 (quat. C), 110.3 (C=C=CH2),

114.7 (CH=CH2), 127.5 (ArCH), 128.4 (ArCH), 129.0 (ArCH), 134.1 (ArC), 138.4

(CH=CH2), 174.0 (CO), 207.4 (C=CH2); m/z (ESI+) 319 ([M + Na]+, 100%); HRMS (ESI+)

found 319.1661, expect 319.1669 for C20H24O2Na.

For cis-1a: υmax / cm-1

3075, 2930, 2861, 1726, 1447, 1223, 1135, 1093, 911, 763, 700; δH

(500 MHz, CDCl3) 1.28 - 1.45 (3H, m, 1H from CH2 + CH2), 1.51 - 1.53 (3H, s, CH3), 1.63 -

1.78 (2H, m, 1H from CH2 + 1H from CH2), 1.78 - 1.91 (2H, m, 1H from CH2 + 1H from

CH2), 1.94 - 2.05 (2H, m, CH2), 2.12 - 2.18 (1H, m, 1H from CH2), 2.28 - 2.37 (1H, m, CH),

4.85 - 5.03 (4H, m, HC=CH2 + C=CH2), 5.67 - 5.77 (1H, m, HC=CH2), 7.18 - 7.30 (5H, m,

ArH); δC (125 MHz, CDCl3) 22.9 (CH2), 26.0 (CH2), 28.7 (CH3), 31.2 (CH2), 32.4 (CH2),

33.7 (CH2), 39.8 (CH), 78.7 (C=CH2), 83.3 (quat. C), 110.6 (C=C=CH2), 114.8 (CH=CH2),

127.6 (ArCH), 128.4 (ArCH), 129.1 (ArCH), 134.7 (ArC), 138.4 (CH=CH2), 173.5 (CO),

207.1 (C=CH2); m/z (ESI+) 297.3 ([M + H]+, 100%); HRMS (ESI+) found 297.1861, expect

297.1849 for C20H25O2.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S9

General Procedure E: Cascade Cyclisation

(4S,4aS,5S,6S,7R,9aS)-4,5,7-Trimethyl-6-phenyldecahydro-4aH-benzo[7]annulene-4a,7-

diol 2a and (1S,2R,3R,4S,5R)-1,3-dimethyl-5-(pent-4-en-1-yl)-2-phenylcycloheptane-1,4-

diol 3a

An oven-dried flask was degassed with N2 and loaded with distilled H2O (2.88 mL, 0.16 mol,

4000 equiv.) and rac-(3R,6S)-6-methyl-3-(pent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-

yl)tetrahydro-2H-pyran-2-one trans-1a (12.0 mg, 0.04 mmol, 1 equiv.) in THF (0.4 mL) and

the mixture was stirred at room temperature for 5 minutes. SmI2 (6.40 mL, 0.62 mmol, 16

equiv.) was added over 30 minutes and the reaction mixture was stirred at room temperature

under a positive pressure of N2 in a sealed flask until decolourisation occurred (48 h). The

flask was opened to air and the reaction was quenched with Rochelle’s salt (3 mL) and

extracted from Et2O (3 × 5 mL). The organic layers were combined and washed with brine

(10 mL) and dried over Na2SO4. Flash column chromatography (10% EtOAc:hexane → 20%

EtOAc:hexane) yielded 3a (4 mg, 33%) and 2a (1.2 mg, 10%) as a colourless oil.

For 2a: υmax / cm-1

3423, 2925, 1450, 1375, 1143, 914, 702; δH (400 MHz, CDCl3) 0.73 (3H,

d, J 6.8, CH3), 1.07 (3H, s, CH3), 1.16 - 1.28 (2H, m, CH2), 1.29 - 1.35 (5H, m, 1H from CH2

+ 1H from CH2 + CH3), 1.37 - 1.54 (4H, m, 1H from CH2 + CH2 + CH), 1.56 - 1.72 (2H, m,

1H from CH2 + CHCH3), 1.80 (1H, dd, J 15.2, 11.7, 1H from CH2), 1.96 - 2.05 (1H, m, 1H

from CH2), 2.21 (1H, q, J 7.8, CHCH3), 3.89 (1H, s, CHPh), 7.21 - 7.29 (1H, m, ArH), 7.29 -

7.35 (2H, m, ArH), 7.37 - 7.41 (2H, m, ArH); δC (100 MHz, CDCl3) 13.3 (CH3), 14.6 (CH3),

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S10

26.0 (CH2), 26.3 (CH2), 28.2 (CH3), 30.8 (2 × CH2), 37.4 (CH), 43.2 (CH2), 43.6 (CHMe),

45.0 (CH), 49.3 (CHPh), 74.8 (quat. C), 76.8 (quat. C), 126.2 (ArCH), 128.3 (ArCH), 129.6

(ArCH), 145.4 (ArC); m/z (ESI-) 301 ([M - H]-, 100%); m/z (ESI+) 267.3 ([M –H2O -

-OH]

+,

100%); HRMS (ESI+) found 325.2151, expect 325.2144 for C20H30O2Na.

For 3a: δH (500 MHz, CDCl3) 0.98 (3H, s, CH3), 1.15 - 1.22 (1H, m, 1H from CH2), 1.24

(3H, d, J 7.3, CH3), 1.27 - 1.41 (1H, m, 1H from CH2), 1.42 - 1.68 (5H, m, 1H from CH2 +

1H from CH2 + CH2 + CH), 1.85 - 1.94 (2H, m, CH2), 1.94 - 2.06 (2H, m, CH2), 2.38 - 2.46

(1H, m, CHCH3), 2.85 (1H, s, CHPh), 3.37 (1H, dd, J 9.1, 4.3, CHOH), 4.85 - 4.99 (2H, m,

HC=CH2), 5.69 - 5.83 (1H, m, HC=CH2), 7.14 - 7.20 (1H, m, ArH), 7.21 - 7.31 (4H, m,

ArH); δC (125 MHz, CDCl3) 13.8 (CH3), 24.3 (CH2), 26.0 (CH2), 29.3 (CH3), 29.7 (CH2),

34.0 (CH2), 34.2 (CH2), 42.2 (CH2), 44.3 (CH), 56.5 (CHPh), 74.2 (quat. C), 80.7 (CHOH),

114.4 (CH=CH2), 126.6 (ArCH), 128.3 (ArCH), 129.6 (ArCH), 139.0 (CH=CH2), 139.6

(ArC); m/z (ESI+) 325.3 ([M + Na]+, 100%); m/z (ESI+) 267.3 ([M – H2O - OH]

+, 100%).

General Procedure F: Cross-metathesis

(E)-Ethyl 2-(3-oxobutyl)-7-phenylhept-6-enoate – S5

As described in general procedure F, stirring ethyl 2-(3-oxobutyl)hept-6-enoate (0.58 g, 2.55

mmol, 1 equiv.), styrene (0.88 mL, 7.65 mmol, 3 equiv.) and Grubbs’ catalyst second

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S11

generation (22 mg, 25.5 µmol, 1 mol%) in CH2Cl2 (6 mL) overnight at reflux with

subsequent work-up and purification by flash column chromatography (toluene → 2%

EtOAc:toluene) yielded the named compound as a colourless oil (0.52 g, 67%); υmax / cm-1

3025, 2934, 1717, 1447, 1367, 1154, 1026, 965, 734, 693; δH (400 MHz, CDCl3) 1.27 (3H, t,

J 7.3, CH2CH3), 1.42 – 1.57 (3H, m, 1 H from CH2 + CH2), 1.64 – 1.75 (1H, m, 1H from

CH2), 1.82 (2H, q, J 7.5, CH2), 2.13 (3H, s, CH3), 2.21 (2H, q, J 6.8, CH2), 2.31 – 2.41 (1H,

m, CH), 2.45 (2H, td, J 7.4, 2.8, CH2), 4.15 (2H, q, J 7.1, CH2CH3), 6.16 (1H, dt, J 15.8, 6.8,

CH2CH=CH), 6.38 (1H, d, J 15.9, CH2CH=CH), 7.2 (1H, tt, J 7.1, 1.5, ArH), 7.27 – 7.34

(4H, m, ArH); δC (100 MHz, CDCl3) 14.3 (CH2CH3), 25.9 (CH2), 26.9 (CH2), 30.0 (CH3),

31.9 (CH2), 32.8 (CH2), 41.1 (CH2), 44.6 (CH), 60.3 (CH2CH3), 125.9 (ArCH), 126.9

(ArCH), 128.4 (ArCH), 130.2 (CH2CH=CH and CH2CH=CH), 137.7 (ArC), 175.7 (CO2Et),

208.0 (CO); m/z (ESI+) 325 ([M + Na]+, 100%); HRMS (ESI+) found 320.2214, expect

320.2220 for C19H30O3N.

rac-(3R,6S)-6-Methyl-3-((E)-5-phenylpent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-

yl)tetrahydro-2H-pyran-2-one – trans-1b

As described in general procedure D, reaction of (E)-ethyl 2-(3-oxobutyl)-7-phenylhept-6-

enoate (0.25 g, 0.33 mmol, 1 equiv.), (3-bromoprop-1-yn-1-yl)benzene (0.20 g, 1.08 mmol,

1.3 equiv.), SmI2 (33.0 mL, 2.69 mmol, 4 equiv.) and NiI2 (20.0 mg, 0.06 mmol, 2 mol %

with respect to SmI2), after work-up and flash column chromatography (5% EtOAc:hexane)

yielded trans-1b as a yellow oil (combined yield for cis and trans isomers: 24%, for trans-

Page 12: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S12

1b: 37 mg, 12%); υmax / cm-1

3025, 2450, 1728, 1493, 1448, 1216, 1092, 1074, 965, 765, 697;

δH (500 MHz, CDCl3) 1.51 - 1.59 (3H, m, 1H from CH2 + CH2), 1.61 (3H, s, CH3), 1.64 -

1.71 (1H, m, 1H from CH2), 1.86 (1H, quin, J 6.7, 1H from CH2), 1.93 - 2.01 (1H, m, 1H

from CH2), 2.12 (1H, sxt, J 6.9, 1H from CH2), 2.19 - 2.29 (3H, m, 1H from CH2 + CH2),

2.40 - 2.48 (1H, m, CH), 5.11 (2H, s, C=CH2), 6.21 (1H, dt, J 15.8, 6.9, CH2CH=CH), 6.39

(1H, d, J 15.8, CH2CH=CH), 7.17 - 7.23 (1H, m, ArH), 7.26 - 7.38 (7H, m, ArH), 7.43 - 7.47

(2H, m, ArH); δC (125 MHz, CDCl3) 22.7 (CH2), 26.7 (CH2), 28.1 (CH3), 31.0 (CH2), 31.9

(CH2), 32.9 (CH2), 38.6 (CH), 78.7 (C=CH2), 82.9 (quat. C), 110.3 (C=C=CH2), 125.9

(ArCH), 126.9 (ArCH), 127.5 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 129.0 (ArCH), 130.2

(CH2CH=CH and CH2CH=CH), 134.1 (ArC), 137.7 (ArC), 174.0 (CO), 207.4 (C=CH2); m/z

(ESI+) 395.2 ([M + Na]+, 100%); HRMS (ESI+) found 395.1996, expect 395.1982 for

C26H28O2Na.

rac-(4R,4aR,5S,6S,7R,9aS)-4-Benzyl-5,7-dimethyl-6-phenyldecahydro-1H-

benzo[7]annulene-4a,7-diol – 2b and (1S,2R,3R,4S,5R)-1,3-dimethyl-2-phenyl-5-((E)-5-

phenylpent-4-en-1-yl)cycloheptane-1,4-diol – 4b

As described in general procedure E, reaction of rac-(3R,6S)-6-methyl-3-((E)-5-phenylpent-

4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-yl)tetrahydro-2H-pyran-2-one trans-1b (35.0 mg,

0.09 mmol, 1 equiv.), H2O (6.80 mL, 0.38 mol, 4000 equiv.) and SmI2 (14.0 mL, 1.50 mmol,

16 equiv.), after work-up and flash column chromatography (10% EtOAc:hexane → 20%

Page 13: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S13

EtOAc:hexane) yielded 4b (3 mg, 8%) and 2b (13 mg, 37%) as a colourless oil and a white

solid, respectively.

For 2b: m. p. 149 – 153 °C (MeOH); υmax / cm-1

3472, 2933, 1718, 1610, 1454, 1369, 755,

699; δH (500 MHz, CDCl3) 1.11 (3H, s, CH3), 1.13 - 1.19 (2H, m, 1H from CH2 + 1H from

CH2), 1.20 - 1.26 (1H, m, 1H from CH2), 1.31 - 1.38 (1H, m, 1H from CH2), 1.41 - 1.50 (5H,

m, CH2 + CH3), 1.52 - 1.65 (2H, m, 1H from CH2 + CH), 1.73 - 1.81 (1H, m, CH), 1.85 (1H,

dd, J 15.3, 11.8, 1H from CH2), 1.99 - 2.13 (3H, m, 1H from CH2Ph + CH2), 2.52 (1H, q, J

7.9, CHCH3), 2.87 (1H, dd, J 13.4, 3.3, 1H from CH2Ph), 3.93 (1H, s, CHPh), 7.05 - 7.09

(2H, m, ArH), 7.14 - 7.18 (1H, m, ArH), 7.22 - 7.26 (3H, m, ArH), 7.31 - 7.35 (2H, m, ArH),

7.40 - 7.44 (2H, m, ArH); δC (125 MHz, CDCl3) 13.3 (CH3) 25.8 (CH2), 26.4 (CH2), 26.6

(CH2), 28.3 (CH3), 30.9 (CH2), 34.7 (CH2), 43.0 (CHMe), 43.1 (CH2), 44.4 (CH), 45.2 (CH),

49.4 (CHPh), 74.7 (quat. C), 77.2 (quat. C), 125.7 (ArCH), 126.3 (ArCH), 128.2 (ArCH),

128.3 (ArCH), 129.1 (ArCH), 129.6 (ArCH), 141.3 (ArC), 145.3 (ArC); HRMS (ESI+) found

401.2473, expect 401.2457 for C26H34O2Na.

For 4b: δH (500 MHz, CDCl3) 0.89 (3H, d, J 6.9, CH3), 0.95 (3H, s, CH3), 1.48 - 1.67 (4H, m,

CH2 + CH2), 1.74 - 1.80 (1H, m, 1H from CH2), 1.85 – 1.91 (1H, m, 1H from CH2), 1.97 -

2.06 (1H, m, 1H from CH2), 2.19 – 2.33 (3H, m, J 6.3, 1H from CH2 + CH2), 2.55 (1H, sxt, J

6.0, CH), 2.77 (1H, s, CHPh), 3.78 (1H, qd, J 6.6, 3.2, CHCH3), 6.20 (1H, dt, J 15.8, 6.9,

CH2CH=CH), 6.39 (1H, d, J 15.8, CH2CH=CH), 6.95 - 6.98 (1H, m, ArH), 7.18 - 7.22 (1H,

m, ArH), 7.23 - 7.39 (8H, m, ArH); δC (125 MHz, CDCl3) 16.2 (CH3), 22.9 (CH2), 26.4

(CH2), 32.0 (CH3), 33.0 (CH2), 34.9 (CH2), 38.5 (CH2), 42.2 (CHMe), 53.8 (CH), 63.2

(CHPh), 73.8 (quat. C), 125.9 (ArCH), 126.8 (ArCH), 127.0 (ArCH), 127.9 (ArCH), 128.5

(ArCH), 130.0 (CH2CH=CH or CH2CH=CH), 130.2 (CH2CH=CH or CH2CH=CH), 130.4

(ArCH), 137.7 (ArC), 137.7 (ArC), 217.2 (CO); m/z (ESI+) 394.5 ([M + NH4]+, 100%);

HRMS (ESI+) found 399.2301, expect 399.2295 for C26H32O2Na.

Page 14: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S14

rac-(4S,4aS,5R,6R,7S,9aR)-7-Methyl-5-(methyl-d)-6-phenyl-4-((S)-phenylmethyl-

d)decahydro-4aH-benzo[7]annulene-5,6-d2-4a,7-diol-d2 – 2b-D4

As described in general procedure E, reaction of rac-(3R,6S)-6-methyl-3-((E)-5-phenylpent-

4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-yl)tetrahydro-2H-pyran-2-one trans-1b (30.0 mg,

0.08 mmol, 1 equiv.), D2O (6.40 mL, 0.32 mol, 4000 equiv.) and SmI2 (6.40 mL, 0.64 mmol,

8 equiv.), after work-up and flash column chromatography (10% EtOAc:hexane → 20%

EtOAc:hexane) yielded 2b-D4 (7 mg, 23%) as a colourless oil; δH (400 MHz, CDCl3) 1.11

(3H, s CH3), 1.12 - 1.19 (2H, m, 1H from CH2 + 1H from CH2), 1.20 - 1.26 (1H, m, 1H from

CH2), 1.32 - 1.37 (1H, m, 1H from CH2), 1.41 - 1.47 (4H, m, CH2 + CDH2), 1.53 - 1.64 (2H,

m, 1H from CH2 + CH), 1.72 - 1.79 (1H, m, CH), 1.84 (1H, dd, J 15.3, 11.7, 1H from CH2),

1.98 - 2.08 (2H, m, 1H, CH2), 2.84 (1H, d, J 2.8, 1H from CDHPh), 7.07 (2H, d, J 7.3, ArH),

7.16 (1H, t, J 7.3, ArH), 7.21 - 7.27 (3H, m, ArH), 7.33 (2H, t, J 7.3, ArH), 7.39 - 7.44 (2H,

m, ArH); δC (125 MHz, CDCl3) 12.8 (t, J 19.1, CDH2), 25.8 (CH2), 26.4 (CH2), 26.6 (CH2),

28.2 (CH3), 30.8 (CH2), 34.4 (t, J 19.1, CDHPh), 42.4 (t, J 17.3, CDCH2D), 43.1 (CH2), 44.3

(CH), 45.2 (CH), 48.9 (t, J 19.1, CDPh), 74.7 (quat. C), 77.2 (quat. C), 125.7 (ArCH), 126.3

(ArCH), 128.2 (ArCH), 128.3 (ArCH), 129.1 (ArCH), 129.6 (ArCH), 141.2 (ArC), 145.3

(ArC); m/z (ESI+) 405.7 ([M + Na]+, 100%); HRMS (ESI+) found 405.2705, expect

405.2708 for C26H30D4O2Na.

Page 15: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S15

Ethyl (E)-2-(3-oxobutyl)-7-(4-(trifluoromethyl)phenyl)hept-6-enoate – S6

As described in general procedure F, ethyl 2-(3-oxobutyl)hept-6-enoate (0.22 g, 0.97 mmol, 1

equiv.), 4-(trifluoromethyl)styrene (0.43 mL, 2.92 mmol, 3 equiv.) and Grubbs’ catalyst

second generation (9.00 mg, 9.72 µmol, 1 mol%) in CH2Cl2 (2 mL) overnight at reflux with

subsequent work-up and purification by flash colum chromatography (toluene → 2%

EtOAc:toluene) yielded the named compound as a colourless oil (0.36 g, 99%); υmax / cm-1

2946, 1716, 1635, 1324, 1162, 1108; δH (500 MHz, CDCl3) 1.27 (3H, t, J 7.3, CH2CH3), 1.44

- 1.57 (3H, m, 1H from CH2 + CH2), 1.64 - 1.74 (1H, m, 1H from CH2), 1.83 (2H, q, J 7.5,

CH2), 2.14 (3H, s, CH3), 2.24 (2H, q, J 6.7, CH2), 2.33 - 2.42 (1H, m, 1H from CH2), 2.45

(1H, qd, J 7.9, 2.5, CH), 4.15 (2H, q, J 7.3, CH2CH3), 6.29 (1H, dt, J 15.8, 6.9, CH2CH=CH),

6.41 (1H, d, J 15.8, CH2CH=CH), 7.42 (2H, d, J 8.2, ArH), 7.54 (2H, d, J 7.9, ArH); δC (125

MHz, CDCl3) 14.3 (CH2CH3), 25.9 (CH2), 26.7 (CH2), 30.0 (CH3), 31.9 (CH2), 32.8 (CH2),

41.0 (CH2), 44.6 (CH), 60.3 (CH2CH3), 125.4 (q, J3 3.6, ArCH), 125.6 (q, J

1 271.6, CF3),

126.0 (ArCH), 129.0 (q, J2 32.7, ArCCF3), 129.1 (CH2CH=CH), 133.1 (CH2CH=CH), 141.1

(ArC), 175.6 (CO2Et), 208.0 (CO); m/z (ESI+) 393.4 ([M + Na]+, 100%); HRMS (ESI+)

found 393.1637, expect 393.1653 for C20H25O3F3Na.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S16

rac-(3R,6S)-6-Methyl-6-(1-phenyl-propa-1,2-dien-1-yl)-3-((E)-5-(4-

(trifluoromethyl)phenyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-one – trans-1c

As described in general procedure D, reaction of ethyl (E)-2-(3-oxobutyl)-7-(4-

(trifluoromethyl)phenyl)hept-6-enoate (0.25 g, 0.68 mmol, 1 equiv.), (3-bromoprop-1-yn-1-

yl)benzene (0.17 g, 0.88 mmol, 1.3 equiv.), SmI2 (27.0 mL, 2.72 mmol, 4 equiv.) and NiI2

(16.0 mg, 0.05 mmol, 2 mol% with respect to SmI2), after work-up and flash column

chromatography (5% EtOAc:hexane) yielded trans-1c as a yellow oil (combined yield for cis

and trans isomers: 24%, for trans-1c: 36 mg, 12%); υmax / cm-1

2934, 1728, 1614, 1324,

1162, 1119, 1067; δH (500 MHz, CDCl3) 1.53 - 1.59 (3H, m, 1H from CH2 + CH2), 1.62 (3H,

s, CH3), 1.64 - 1.72 (1H, m, 1H from CH2), 1.86 (1H, quin, J 6.4, 1H from CH2), 1.91 - 2.01

(1H, m, 1H from CH2), 2.12 (1H, sxt, J 6.9, 1H from CH2), 2.20 - 2.30 (3H, m, 1H from CH2

+ CH2), 2.40 - 2.48 (1H, m, CH), 5.11 (2H, s, C=CH2), 6.31 (1H, dt, J 15.7, 6.7,

CH2CH=CH), 6.42 (1H, d, J 15.9, CH2CH=CH), 7.24 - 7.30 (1H, m, ArH), 7.34 (2H, t, J 7.6,

ArH), 7.43 (4H, dd, J 13.1, 7.7, ArH), 7.54 (2H, d, J 8.1, ArH); δC (125 MHz, CDCl3) 22.7

(CH2), 26.4 (CH2), 28.1 (CH3), 31.0 (CH2), 31.8 (CH2), 32.9 (CH2), 38.6 (CH), 78.7

(C=CH2), 83.0 (quat. C), 110.2 (C=C=CH2), 124.2 (q, J1 271.6, CF3), 125.4 (q, J

3 3.6,

ArCH), 126.0 (ArCH), 127.5 (ArCH), 128.4 (ArCH), 128.6 (q, J2 32.7, ArCCF3), 128.9

(CH2CH=CH), 129.0 (ArCH), 133.1 (CH2CH=CH), 134.0 (ArC), 141.1 (ArC), 174.0 (CO),

207.4 (C=CH2); m/z (ESI+) 463.2 ([M + Na]+, 100%); HRMS (ESI+) found 463.1848, expect

463.1855 for C27H27O2F3Na.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S17

rac-(4S,4aS,5R,6R,7S,9aR)-5,7-Dimethyl-6-phenyl-4-(4-

(trifluoromethyl)benzyl)decahydro-4aH-benzo[7]annulene-4a,7-diol – 2c

As described in general procedure E, reaction of rac-(3R,6S)-6-methyl-6-(1-phenyl-propa-

1,2-dien-1-yl)-3-((E)-5-(4-(trifluoromethyl)phenyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-one

trans-1c (40.0 mg, 0.09 mmol, 1 equiv.), H2O (6.50 mL, 0.36 mol, 4000 equiv.) and SmI2

(7.30 mL, 0.73 mmol, 8 equiv.), after work-up and flash column chromatography (10%

EtOAc:hexane → 20% EtOAc:hexane) yielded 2c (10 mg, 24%) as a colourless oil; υmax /

cm-1

3458, 2953, 2872, 1623, 1451, 1321, 1186, 1121, 1085; δH (500 MHz, CDCl3) 1.12 (3H,

m, CHCH3), 1.14 - 1.19 (2H, m, 1H from CH2 + 1H from CH2), 1.22 - 1.27 (2H, m 1H from

CH2 + 1H from CH2), 1.40 - 1.51 (5H, m, CH2 + CH3), 1.53 - 1.65 (2H, m, 1H from CH2 +

CH), 1.78 (1H, tt, J 11.3, 4.1, CH), 1.85 (1H, dd, J 15.3, 11.8, 1H from CH2), 1.99 - 2.07 (2H,

m, CH2), 2.19 (1H, dd, J 13.2, 11.3, 1H from CH2Ph), 2.48 (1H, q, J 7.6, CHCH3), 2.91 (1H,

dd, J 13.2, 2.8, 1H from CH2Ph), 3.91 (1H, s, CHPh), 7.18 (2H, d, J 7.9, ArH-CF3), 7.23 -

7.27 (1H, ArH), 7.34 (2H, t, J 7.6, ArH), 7.41 (2H, d, J 7.3, ArH), 7.50 (2H, d, J 7.9, ArH-

CF3); δC (125 MHz, CDCl3) 13.2 (CH3), 25.7 (CH2), 26.4 (CH2), 26.6 (CH2), 28.3 (CH3), 30.8

(CH2), 34.7 (CH2), 42.9 (CHMe), 43.1 (CH2), 44.2 (CH), 45.1 (CH), 49.4 (CHPh), 74.7(quat.

C), 77.2 (quat. C), 125.1 (q, J3 3.6, ArCH), 125.4 (q, J

1 271.6, CF3) 126.4 (ArCH), 128.2 (q,

J2 31.8, ArCCF3), 128.4 (ArCH), 129.4 (ArCH), 129.6 (ArCH), 145.2 (ArC), 145.6 (ArC);

m/z (ESI+) 469.5 ([M + Na]+, 100%); HRMS (ESI+) found 469.2321, expect 469.2330 for

C27H33O2F3Na.

Page 18: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S18

Ethyl (E)-7-(4-bromophenyl)-2-(3-oxobutyl)hept-6-enoate – S7

As described in general procedure F, ethyl 2-(3-oxobutyl)hept-6-enoate (0.20 g, 0.88 mmol, 1

equiv.), Hoveyda-Grubbs II catalyst (5.50 mg, 8.80 µmol, 1 mol%) and 4-bromostyrene (0.49

g, 2.65 mmol, 3 equiv.) in CH2Cl2 (5 mL) after work-up and column chromatography on

silica gel eluting with (petroleum ether -10% EtOAc:petroleum ether) gave the title

compound as a yellow oil (0.15 g, 45%); νmax /cm-1

2935, 1716, 1487, 1445, 1401, 1366,

1154, 1096, 1072, 1026; δH (400 MHz, CDCl3) 1.27 (3H, t, J 7.1, CH2CH3), 1.41 - 1.56 (3H,

m, 1H from CH2 + CH2), 1.61 - 1.74 (1H, m, 1H from CH2), 1.78 - 1.86 (2H, m, CH2), 2.13

(3H, s, CH3), 2.17 - 2.24 (2H, m, CH2), 2.32 - 2.40 (1H, m, CH), 2.41 - 2.49 (2H, m,

CH2CO), 4.15 (2H, q, J 7.1, CH2CH3), 6.12 - 6.22 (1H, m, CH=CHPh), 6.27 - 6.36 (1H, m,

CH=CHPh), 7.20 (2H, d, J 8.6, ArH), 7.41 (2H, d, J 8.6, ArH); δC (100 MHz, CDCl3) 14.3

(CH3), 25.9 (CH2), 26.8 (CH2), 30.0 (CH3), 31.9 (CH2), 32.8 (CH2), 41.1 (CH2), 44.6 (CH),

60.3 (CH2CH3), 120.5 (ArC), 127.5 (ArCH), 129.1 (CH2CH=CH), 131.1 (CH2CH=CH),

131.5 (ArCH), 136.6 (ArC), 175.6 (CO2Et), 207.9 (CO); m/z (ESI+) 381.0 ([M+H]+, 100%).

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S19

rac-(3R,6S)-3-((E)-5-(4-Bromophenyl)pent-4-en-1-yl)-6-methyl-6-(1-phenyl-2l5-propa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1d

As described in general procedure D, reaction of ethyl (E)-7-(4-bromophenyl)-2-(3-

oxobutyl)hept-6-enoate (0.24 g, 0.63 mmol, 1 equiv.), (3-bromoprop-1-yn-1-yl)benzene (0.16

g, 0.82 mmol, 1.3 equiv.), SmI2 (23.0 mL, 2.22 mmol, 3.5 equiv.) and NiI2 (14.0 mg, 0.04

mmol, 2 mol% with respect to SmI2), after work-up and flash column chromatography (5%

EtOAc:hexane) yielded trans-1d as a yellow oil (combined yield for cis and trans isomers:

22%, for trans-1d: 30 mg, 11%); υmax / cm-1

2934, 1726, 1487, 1216, 1072; δH (500 MHz,

CDCl3) 1.51 - 1.59 (3H, m, 1H from CH2 + CH2), 1.62 (3H, m, CH3), 1.63 - 1.71 (1H, m, 1H

from CH2), 1.86 (1H, quin, J 6.6, 1H from CH2), 1.92 - 1.98 (1H, m, 1H from CH2), 2.11

(1H, sxt, J 7.3, 1H from CH2), 2.19 - 2.27 (3H, m, 1H from CH2 + CH2), 2.40 - 2.47 (1H, m,

CH), 5.12 (2H, s, C=CH2), 6.20 (1H, dt, J 15.8, 6.9, CH2CH=CH), 6.32 (1 H, d, J 15.8,

CH2CH=CH), 7.18 - 7.21 (2H, m, ArH), 7.26 - 7.30 (1H, m, ArH), 7.31 - 7.35 (2H, m, ArH),

7.39 - 7.42 (2H, m, ArH), 7.43 - 7.46 (2H, m, ArH); δC (125 MHz, CDCl3) 22.7 (CH2) 26.5

(CH2) 28.1 (CH3) 31.0 (CH2) 31.9 (CH2) 32.9 (CH2) 38.6 (CH) 78.7 (C=CH2) 83.0 (quat. C)

110.3 (C=C=CH2) 120.5 (ArC) 127.5 (ArCH) 128.4 (ArCH) 129.0 (ArCH) 129.1

(CH2CH=CH) 131.1 (CH2CH=CH) 131.5 (ArCH) 134.0 (ArC) 136.6 (ArC) 173.9 (CO)

207.4 (C=CH2); m/z (ESI+) 485.5 ([M + K]+, 100%); HRMS (ESI+) found 451.1267, expect

451.1267 for C26H28O2Br.

Page 20: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S20

rac-(4S,4aS,5R,6R,7S,9aR)-4-(4-Bromobenzyl)-5,7-dimethyl-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2d

As described in general procedure E, reaction of rac-(3R,6S)-3-((E)-5-(4-bromophenyl)pent-

4-en-1-yl)-6-methyl-6-(1-phenyl-propa-1,2-dien-1-yl)tetrahydro-2H-pyran-2-one trans-1d

(70 mg, 0.16 mmol, 1 equiv.), H2O (11.2 mL, 0.62 mol, 4000 equiv.) and SmI2 (12.5 mL,

1.24 mmol, 8 equiv.), after work-up and flash column chromatography (10% EtOAc:hexane

→ 20% EtOAc:hexane) yielded 2d (14 mg, 20%) as a white solid; m. p. 151 – 155 °C

(MeOH); υmax / cm-1

3472, 2962, 2924, 1622, 1492, 1470, 1432, 1016; δH (500 MHz, CDCl3)

1.12 (3H, s, CH3), 1.14 - 1.16 (1H, m, 1H from CH2), 1.21 - 1.26 (1H, m, 1H from CH2), 1.27

– 1.33 (1H, m, 1H from CH2), 1.43 (3H, d, J 7.6, CH3), 1.45 - 1.48 (2H, m, CH2), 1.52 - 1.59

(2H, m, 1H from CH2 + CH), 1.60 - 1.65 (1H, m, 1H from CH2), 1.72 (1H, tt, J 7.6, 3.7, CH),

1.84 (1H, dd, J 15.3, 11.8, 1H from CH2), 1.99 - 2.11 (3H, m, 1H from CH2Ph + CH2), 2.47

(1H, q, J 7.7, CHCH3), 2.80 (1H, dd, J 13.6, 3.5, 1H from CH2Ph), 3.90 (1H, s, CHPh), 6.94

(2H, d, J 8.2, ArH), 7.23 - 7.28 (2H, m, ArH), 7.31 - 7.38 (4H, m, ArH), 7.41 (2H, d, J 7.3,

ArH); δC (125 MHz, CDCl3) 13.2 (CH3), 25.7 (CH2), 26.4 (CH2), 26.5 (CH2), 28.3 (CH3),

30.8 (CH2), 34.2 (CH2), 42.9 (CHMe), 43.1 (CH2), 44.3 (CH), 45.1 (CH), 49.4 (CHPh), 74.7

(quat. C), 77.2 (quat. C), 119.4 (ArC), 126.4 (ArCH), 128.4 (ArCH), 129.6 (ArCH), 130.8

(ArCH), 131.2 (ArCH), 140.3 (ArC), 145.2 (ArC); m/z (ESI+) 479.3 ([M + Na]+, 100%);

HRMS (ESI+) found 479.1570, expect 479.1562 for C26H33O2BrNa.

Page 21: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S21

Ethyl (E)-2-(3-oxobutyl)-7-(p-tolyl)hept-6-enoate – S8

As described in general procedure F, ethyl 2-(3-oxobutyl)hept-6-enoate (0.60 g, 2.65 mmol, 1

equiv.), 4-methylstyrene (1.00 g, 7.96 mmol, 3 equiv.) and Grubbs’ catalyst second

generation (45.0 mg, 53.1 µmol, 1 mol%) in CH2Cl2 (10 mL) overnight at reflux with

subsequent work-up and purification by flash colum chromatography (toluene → 2%

EtOAc:toluene) yielded the named compound as a colourless oil (0.58 g, 69%); υmax / cm-1

2934, 1717, 1512, 1446, 1367, 1155; δH (500 MHz, CDCl3) 1.27 (3H, t, J 7.3, CH2CH3), 1.44

- 1.54 (3H, m, 1H from CH2 + CH2), 1.64 - 1.73 (1H, m, 1H from CH2), 1.82 (2H, q, J 7.3,

CH2), 2.13 (3H, s, CH3), 2.20 (2H, q, J 6.7, CH2), 2.33 (3H, s, CH3), 2.34 - 2.39 (1H, m, 1H

from CH2), 2.44 (2H, td, J 7.5, 3.9, CH), 4.15 (2H, q, J 7.3, CH2CH3), 6.13 (1H, dt, J 15.7,

7.0, CH2CH=CH), 6.34 (1H, d, J 15.8, CH2CH=CH), 7.10 (2H, d, J 7.9, ArH), 7.23 (2H, d, J

8.2, ArH); δC (125 MHz, CDCl3) 14.3 (CH2CH3), 21.1 (ArCH3), 25.9 (CH2), 27.0 (CH2), 29.9

(CH3), 31.8 (CH2), 32.7 (CH2), 41.1 (CH2), 44.6 (CH), 60.2 (CH2CH3), 125.8 (ArCH), 129.1

(CH2CH=CH + CH2CH=CH), 130.0 (ArCH), 134.8 (ArC), 136.5 (ArC), 175.7 (CO2Et),

208.0 (CO); m/z (ESI+) 317.5 ([M + H]+, 100%); HRMS (ESI+) found 339.1931, expect

339.1936 for C20H28O3Na.

Page 22: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S22

rac-(3R,6S)-6-Methyl-6-(1-phenyl-2l5-propa-1,2-dien-1-yl)-3-((E)-5-(p-tolyl)pent-4-en-1-

yl)tetrahydro-2H-pyran-2-one – trans-1e

As described in general procedure D, reaction of ethyl (E)-2-(3-oxobutyl)-7-(p-tolyl)hept-6-

enoate (0.23 g, 0.71 mmol, 1 equiv.), (3-bromoprop-1-yn-1-yl)benzene (0.18 g, 0.95 mmol,

1.3 equiv.), SmI2 (25.0 mL, 2.49 mmol, 3.5 equiv.) and NiI2 (16.0 mg, 0.05 mmol, 2 mol%

with respect to SmI2), after work-up and flash column chromatography (5% EtOAc:hexane)

yielded trans-1e as a yellow oil (combined yield for cis and trans isomers: 20%, for trans-1e:

28 mg, 10%); υmax / cm-1

2923, 1726, 1512, 1492, 1446, 1215, 1091; δH (400 MHz, CDCl3)

1.51 - 1.55 (2H, m, CH2), 1.59 - 1.71 (5H, m, CH2 + CH3), 1.85 (1H, quin, J 6.6, 1H from

CH2), 1.92 - 2.00 (1H, m, 1H from CH2), 2.11 (1H, sxt, J 6.8, 1H from CH2), 2.18-2.25 (3H,

m, 1H from CH2 + CH2), 2.33 (3H, s, ArCH3), 2.39 - 2.47 (1H, m, CH), 5.11 (2H, s, C=CH2),

6.17 (1H, dt, J 15.6, 7.1, CH2CH=CH), 6.35 (1H, d, J 15.9, CH2CH=CH), 7.10 (2H, d, J 7.8,

ArH), 7.23 (2H, d, J 8.3, ArH), 7.28 - 7.30 (1H, m, ArH), 7.31 - 7.36 (2H, m, ArH), 7.43 -

7.46 (2H, m, ArH); δC (125 MHz, CDCl3) 21.1 (ArCH3), 22.6 (CH2), 26.7 (CH2), 28.1 (CH3),

31.0 (CH2), 31.8 (CH2), 32.9 (CH2), 38.6 (CH), 78.7 (C=CH2), 82.9 (quat. C), 110.2

(C=C=CH2), 125.8 (ArCH), 127.5 (ArCH), 128.4 (ArCH), 128.9 (ArCH), 129.1 (ArCH),

129.2 (CH2CH=CH), 130.0 (CH2CH=CH), 134.0 (ArC), 134.9 (ArC), 136.6 (ArC), 174.0

(CO), 207.4 (C=CH2); m/z (ESI+) 387.2 ([M + H]+, 100%); HRMS (ESI+) found 387.2310,

expect 387.2319 for C27H31O2.

Page 23: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S23

rac-(4S,4aS,5R,6R,7S,9aR)-5,7-Dimethyl-4-(4-methylbenzyl)-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2e

As described in general procedure E, reaction of rac-(3R,6S)-6-methyl-6-(1-phenyl-2l5-

propa-1,2-dien-1-yl)-3-((E)-5-(p-tolyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-one trans-1e

(28.0 mg, 0.07 mmol, 1 equiv.), H2O (5.20 mL, 0.29 mol, 4000 equiv.) and SmI2 (5.80 mL,

0.58 mmol, 8 equiv.), after work-up and flash column chromatography (10% EtOAc:hexane

→ 20% EtOAc:hexane) yielded 2e (7 mg, 26%) as a yellow oil; υmax / cm-1

3486, 2965, 2879,

1514, 1479, 1398, 1085; δH (400 MHz, CDCl3) 1.11 (3H, s, CH3), 1.12 - 1.18 (1H, m, 1H

from CH2), 1.19 - 1.26 (1H, m, 1H from CH2), 1.29 - 1.34 (1H, m, 1H from CH2), 1.39 - 1.51

(5H, m, CH2 + CH3), 1.53 - 1.63 (3H, m, 1H from CH2 + 1H from CH2 + CH), 1.70 - 1.77

(1H, m, CH), 1.85 (1H, dd, J 15.4, 11.9, 1H from CH2), 1.98 - 2.09 (3H, m, 1H from CH2Ph

+ CH2), 2.31 (3H, s, ArCH3), 2.51 (1H, q, J 7.6, CHCH3), 2.82 (1H, dd, J 13.4, 3.3, 1H from

CH2Ph), 3.92 (1H, s, CHPh), 6.95 (2H, d, J 7.8, ArH), 7.06 (2H, d, J 7.8, ArH), 7.22 - 7.27

(1H, m, ArH), 7.33 (2H, dd, J 7.8, 7.1, ArH), 7.42 (2H, d, J 7.1, ArH); δC (125 MHz, CDCl3)

13.3 (CH3), 21.0 (ArCH3), 25.8 (CH2), 26.4 (CH2), 26.6 (CH2), 28.3 (CH3), 30.9 (CH2), 34.2

(CH2), 43.0 (CHMe), 43.2 (CH2), 44.4 (CH), 45.2 (CH), 49.4 (CHPh), 74.7 (quat. C), 77.2

(quat. C), 126.3 (ArCH), 128.3 (ArCH), 128.9 (ArCH), 129.0 (ArCH), 129.6 (ArCH), 135.1

(ArC), 138.0 (ArC), 145.3 (ArC); m/z (ESI+) 415.5 ([M + Na]+, 100%); HRMS (ESI+) found

415.2626, expect 415.2613 for C27H36O2Na.

Page 24: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S24

Ethyl (E)-7-(2-chlorophenyl)-2-(3-oxobutyl)hept-6-enoate – S9

As described in general procedure F, ethyl 2-(3-oxobutyl)hept-6-enoate (0.30 g, 1.33 mmol, 1

equiv.), 2-chlorostyrene (0.51 mL, 3.98 mmol, 3 equiv.) and Grubbs’ catalyst second

generation (12.0 mg, 13.3 µmol, 1 mol%) in CH2Cl2 (3 mL) overnight at reflux with

subsequent work-up and purification by flash colum chromatography (toluene → 2%

EtOAc:toluene) yielded the named compound as a colourless oil (0.29 g, 66%); υmax / cm-1

2935, 1718, 1470, 1440, 1367, 1156; δH (400 MHz, CDCl3) 1.27 (3H, t, J 7.1, CH2CH3), 1.43

- 1.58 (3H, m, 1H from CH2 + CH2), 1.64 - 1.75 (1H, m, 1H from CH2), 1.79 - 1.87 (2H, m,

CH2), 2.14 (3H, s, CH3), 2.26 (2H, q, J 6.6, CH2), 2.33 - 2.42 (1H, m, CH), 2.42 - 2.49 (2H,

m, CH2), 4.16 (2H, q, J 7.2, CH2CH3), 6.11 - 6.22 (1H, m, CH2CH=CH), 6.75 (1H, d, J 16.1,

CH2CH=CH), 7.09 - 7.23 (2H, m, ArH), 7.33 (1H, d, J 7.8, ArH), 7.49 (1H, d, J 7.7, ArH); δC

(100 MHz, CDCl3) 14.4 (CH3), 26.0 (CH2), 26.8 (CH2), 30.0 (CH3), 31.9 (CH2), 33.0 (CH2),

41.1 (CH2), 44.6 (CH), 60.3 (CH2CH3), 126.5 (2 × CH=CHPh), 126.6 (ArCH), 126.8

(ArCH), 128.0 (ArCH), 129.6 (ArCH), 133.2 (ArC), 135.8 (ArC), 175.7 (CO2Et), 208.0

(CO); m/z (ESI+) 337.3 ([M + H]+, 100%); HRMS (ESI+) found 359.1377, expect 359.1390

for C19H25O3ClNa.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S25

rac-(3R,6S)-3-((E)-5-(2-Chlorophenyl)pent-4-en-1-yl)-6-methyl-6-(1-phenyl-2l5-propa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1f

As described in general procedure D, reaction of ethyl ethyl (E)-7-(2-chlorophenyl)-2-(3-

oxobutyl)hept-6-enoate (0.36 g, 1.07 mmol, 1 equiv.), (3-bromoprop-1-yn-1-yl)benzene (0.27

g, 1.39 mmol, 1.3 equiv.), SmI2 (34.0 mL, 3.74 mmol, 3.5 equiv.) and NiI2 (16.0 mg, 74.6

µmol, 2 mol% with respect to SmI2), after work-up and flash column chromatography (5%

EtOAc:hexane) yielded trans-1f as a yellow oil (combined yield for cis and trans isomers:

20%, for trans-1f: 44 mg, 10%); υmax / cm-1

2929, 1945, 1721, 1492, 1469, 1215, 1074; δH

(400 MHz, CDCl3) 1.43 - 1.56 (6H, m, 1H from CH2 + CH2 + CH3), 1.55 - 1.64 (1H, m, 1H

from CH2), 1.74 - 1.82 (1H, m, 1H from CH2), 1.84 - 1.92 (1H, m, 1H from CH2), 2.03 (1 H,

sxt, J 6.7, 1H from CH2), 2.11 - 2.23 (3H, m, 1H from CH2 + CH2), 2.32 – 2.39 (1H, m, CH),

5.03 (2H, s, C=CH2), 6.07 - 6.17 (1H, m, CH2CH=CH), 6.67 (1H, d, J 15.7, CH2CH=CH),

7.05 (1H, t, J 7.3, ArH), 7.11 (1H, t, J 7.3 ArH), 7.15 - 7.21 (2H, m, ArH), 7.24 - 7.28 (2H,

m, ArH), 7.36 (2H, d, J 7.5, ArH), 7.41 (1H, d, J 7.6 ArH); δC (125 MHz, CDCl3) 22.9 (CH2),

26.8 (CH2), 28.4 (CH3), 31.5 (CH2), 32.3 (CH2), 33.2, (CH2), 38.6 (CH), 78.9 (C=CH2), 83.0

(quat. C), 110.5 (C=C=CH2), 126.4 (CH2CH=CH), 126.5 (CH2CH=CH), 126.8 (ArCH),

127.7 (ArCH), 128.1 (ArCH), 128.6 (ArCH), 129.2 (ArCH), 129.5 (ArCH), 132.7 (ArCH),

133.3 (ArC), 134.1 (ArC), 135.7 (ArC), 174.5 (CO), 208.3 (C=CH2); m/z (ESI+) 407.3 ([M +

H]+, 100%); HRMS (ESI+) found 429.1603, expect 429.1592 for C26H27O2ClNa.

Page 26: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S26

rac-(4S,4aS,5R,6R,7S,9aR)-4-(2-Chlorobenzyl)-5,7-dimethyl-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2f

As described in general procedure E, reaction of rac-(3R,6S)-6-methyl-6-(1-phenyl-2l5-

propa-1,2-dien-1-yl)-3-((E)-5-(p-tolyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-one trans-1f

(38.0 mg, 0.09 mmol, 1 equiv.), H2O (6.70 mL, 0.37 mol, 4000 equiv.) and SmI2 (7.5 mL,

0.75 mmol, 8 equiv.), after work-up and flash column chromatography (10% EtOAc:hexane

→ 20% EtOAc:hexane) yielded 2f (7 mg, 17%) as a white solid; m. p. 149 – 155 °C

(MeOH); υmax / cm-1

3329, 2918, 2852, 1448, 1386, 1264; δH (500 MHz, CDCl3) 1.11 (3H, s,

CH3), 1.12 - 1.20 (2H, m, 1H from CH2 + 1H from CH2), 1.22 - 1.24 (1H, m, 1H from CH2),

1.42 - 1.47 (2H, m, CH2), 1.48 (3H, d, J 7.6, CH3), 1.54 - 1.60 (2H, m, 1H from CH2 + CH),

1.86 (1H, dd, J 15.4, 11.7, 1H from CH2), 1.98 - 2.07 (4H, m, 1H from CH2 + CH + CH2),

2.37 (1 H, dd, J 13.1, 11.2, 1H from CH2Ph), 2.46 (1H, q, J 7.9, CHCH3), 2.94 (1H, dd, J

13.2, 4.4, 1H from CH2Ph), 3.91 (1H, s, CHPh), 7.05 - 7.08 (1H, m, ArH), 7.10 - 7.13 (2H,

m, ArH), 7.23 - 7.26 (1H, m, ArH), 7.29 - 7.31 (1H, m, ArH), 7.32 - 7.36 (2H, m, ArH), 7.40

- 7.44 (2H, m, ArH); δC (125 MHz, CDCl3)* 13.3 (CH3), 25.7 (CH2), 26.4 (CH2), 26.4 (CH2),

28.3 (CH3), 30.7 (CH2), 32.7 (CH2), 41.7 (CHMe), 43.0 (CH2), 43.1 (CH), 45.1 (CH), 49.5

(CHPh), 126.3 (ArCH), 126.4 (ArCH), 127.2 (ArCH), 128.3 (ArCH), 129.4 (ArCH), 129.6

(ArCH), 131.9 (ArCH), 134.2 (ArC), 138.7 (ArC), 145.3 (ArC); m/z (ESI+) 435.7 ([M +

Na]+, 100%). *two quaternary carbons not observed.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S27

Ethyl (E)-4,4-dimethylhepta-2,6-dienoate – S10

An oven-dried round bottom flask was flushed with N2 and loaded with

(carbethoxymethylene)triphenylphosphorane (12.0 g, 34.0 mmol, 1.7 equiv.) and dry toluene

(60 mL). To the stirred solution was added 2,2-dimethyl-4-pentenal (1.36 mL, 10.0 mmol, 1

equiv.) and the resulting solution was heated at 80 °C overnight. After cooling to room

temperature, the solvent was removed in vacuo and flash column chromatography (5%

Et2O:hexane) yielded S10 (3.31 g, 91%) as a colourless oil; υmax / cm-1

3091, 2982, 1707,

1679, 1382, 1302, 1279, 1186, 1018; δH (400 MHz, CDCl3) 1.01 (6H, s, 2 × CH3), 1.24 (3H,

t, J 7.2, CH2CH3), 2.06 (2H, dt, J 7.4, 1.1, CH2), 4.14 (2H, q, J 7.1, CH2CH3), 4.93 - 5.03

(2H, m, CH=CH2), 5.59 - 5.72 (2H, m, CH=CH2 + CH=CHCO2Et), 6.89 (1H, d, J 15.9,

CH=CHCO2Et); δC (100 MHz, CDCl3) 14.1 (CH3), 26.0 (2 × CH3), 36.6 (quat. C), 46.3

(CH2), 60.0 (CH2CH3), 117.6 (CH=CH2), 117.8 (CH=CHCO2Et), 134.1 (CH=CH2), 157.4

(CH=CHCO2Et), 166.9 (CO2Et); m/z (ESI+) 183.1 ([M + H]+, 100%); HRMS (ESI+) found

205.1205, expect 205.1204 for C11H18O2Na.

Methyl 4,4-dimethylhept-6-enoate – S11

Magnesium powder (2.70 g, 0.11 mol, 8 equiv.) was added slowly to a stirred solution of

ethyl (E)-4,4-dimethylhepta-2,6-dienoate (2.50 g, 13.7 mmol, 1 equiv.) in dry MeOH (130

mL) in an oven-dried round bottom flask flushed with N2.The reaction was stirred at room

temperature overnight and more magnesium powder (0.67 g, 27.5 mmol, 2 equiv.) was

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S28

added. After stirring for an additional 2 hours, the reaction was neutralised with 2 M HCl and

EtOAc was added (150 mL). The layers were separated and the aqueous layer was washed

with EtOAc (150 mL). The organic layers were combined, washed with brine (150 mL) and

dried over MgSO4. Concentration in vacuo and filtration through silica gel yielded S11 (1.21

g, 53%) as a crude colourless oil, which was taken through to the next step; δH (400 MHz,

CDCl3) 0.87 (6H, s, 2 × CH3), 1.53 - 1.59 (2H, m, CH2CH2CO2CH3), 1.95 (2H, dt, J 7.4, 1.1,

CH2CH=CH2), 2.25 - 2.31 (2H, m, CH2CO2CH3), 3.66 (3H, s, CO2CH3), 4.97 - 5.07 (2H, m,

CH=CH2), 5.80 (1H, m, CH=CH2); δC (100 MHz, CDCl3) 26.5 (2 × CH3), 29.3 (CH2), 32.7

(quat. C), 36.4 (CH2), 46.2 (CH2), 51.5 (CO2CH3), 117.1 (CH=CH2), 135.0 (CH=CH2), 174.7

(CO2Me).

Methyl (E)-4,4-dimethyl-7-phenylhept-6-enoate – S12

As described in general procedure F, methyl 4,4-dimethylhept-6-enoate (1.20 g, 7.05 mmol, 1

equiv.), styrene (2.40 mL, 21.2 mmol, 3 equiv.) and Grubb’s catalyst second generation (60.0

mg, 70.5 µmol, 1 mol%) in CH2Cl2 (18 mL) overnight at reflux with subsequent work-up and

purification by flash colum chromatography (toluene → 2% EtOAc:toluene) yielded the

named compound as a colourless oil (0.8 g, 46%); υmax / cm-1

3042, 2979, 1744, 1465, 1214,

1180; δH (400 MHz, CDCl3) 0.93 (6H, s, 2 × CH3), 1.60 - 1.67 (2H, m, CH2CH2CO2CH3),

2.12 (2H, dd, J 7.5, 0.8, CH2CH), 2.30 - 2.36 (2H, m, CH2CO2CH3), 3.68 (3H, s, CO2CH3),

6.18 - 6.29 (1H, m, CH=CHPh), 6.39 (1H, d, J 15.5, CH=CHPh), 7.22 (1H, t, J 7.2, ArH),

7.31 (2H, t, J 7.5, ArH), 7.37 (2H, d, J 7.3, ArH); δC (100 MHz, CDCl3) 26.6 (2 × CH3), 29.4

(CH2), 33.5 (quat. C), 36.5 (CH2), 45.4 (CH2), 51.6 (CO2CH3), 126.0 (ArCH), 126.9 (ArCH),

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S29

127.0 (CH=CHPh), 128.5 (ArCH), 132.4 (CH=CHPh), 137.7 (ArC), 174.7 (CO2Me); m/z

(ESI+) 269.3 ([M + Na]+, 100%).

2-(2-Iodoethyl)-2-methyl-1,3-dioxolane – S133

To a rapidly stirred solution of methyl vinyl ketone (3.00 mL, 36.0 mmol, 1 equiv.) and NaI

(6.50 g, 43.3 mmol, 1.2 equiv.) in MeCN (36 mL) was quickly added TMSCl (5.50 mL, 43.3

mmol, 1.2 equiv.) and the mixture was stirred for 25 minutes. Ethylene glycol (2.40 mL, 43.3

mmol, 1.2 equiv.) was added quickly and the reaction was stirred vigorously for another 25

minutes. The reaction mixture was then poured into a separating funnel containing 5%

NaHCO3 (15 mL) and hexane (60 mL), creating an aqueous bottom layer, the reaction

mixture in the middle and a top hexane layer. The bottom layer was removed and the organic

layers washed with 5% sodium thiosulfate (15 mL). The aqueous layers were combined and

extracted with EtOAc (2 × 60 mL). The organic layers were combined and dried over

MgSO4. The solvent was removed in vacuo, keeping the water bath below 25 °C, and flash

column chromatography (5% EtOAc:hexane) yielded the named compound as an orange oil

(1.2 g, 15%); δH (400 MHz, CDCl3) 1.29 - 1.33 (3H, m, CH3), 2.26 - 2.34 (2H, m, CH2), 3.13

- 3.20 (2H, m, CH2), 3.87 - 4.02 (4H, m, -OCH2CH2O-).

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S30

Methyl (E)-4,4-dimethyl-2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-7-phenylhept-6-enoate –

S14

As described in general procedure A, alkylation of methyl (E)-4,4-dimethyl-7-phenylhept-6-

enoate (0.22 g, 0.89 mmol, 1 equiv.) using LDA (0.75 M, 1.3 mL, 0.98 mmol, 1.1 equiv.),

then 2-(2-iodoethyl)-2-methyl-1,3-dioxolane (0.28 g, 1.22 mmol, 1.36 equiv.) and HMPA

(0.2 mL), after work-up and purification yielded S14 as an orange oil (75 mg, 17%); υmax /

cm-1

2983, 2893, 1714, 1479, 1392, 1210, 1181, 1080; δH (500 MHz, CDCl3) 0.89 (3H, s, J

4.4, CH3), 0.90 (3H, s, J 4.4, CH3), 1.29 (3H, s, CH3), 1.33 (1H, dd, J 14.2, 2.2, 1H from

CH2), 1.51 - 1.58 (2H, m, 1H from CH2 + 1H from CH2), 1.64 - 1.71 (2H, m, 1 H from CH2 +

1 H from CH2), 1.87 (1H, dd, J 14.2, 9.8, 1H from CH2), 2.10 (2H, dd, J 7.6, 0.9, CH2), 2.42 -

2.50 (1H, m, CH), 3.67 (3H, s, CO2CH3), 3.86 - 3.96 (4H, m, -OCH2CH2O-), 6.18 - 6.26 (1H,

m, CH=CHPh), 6.37 (1H, d, J 15.8, CH=CHPh), 7.21 (1H, tt, J 7.3, 1.3, ArCH), 7.31 (2H, t, J

7.3, ArCH), 7.36 (2H, d, J 7.3, ArCH); δC (125 MHz, CDCl3) 23.8 (CH3), 26.7 (CH3), 26.9

(CH3), 29.3 (CH2), 34.2 (quat. C), 36.7 (CH2), 41.4 (CH), 44.4 (CH2), 45.9 (CH2), 51.5

(CO2CH3), 64.6 (2 × -OCH2CH2O-), 109.6 (C-OCH2CH2O-), 126.0 (ArCH), 126.9 (ArCH),

127.2 (CH=CHPh), 128.5 (ArCH), 132.4 (CH=CHPh), 137.7 (ArC), 177.6 (CO2Me); m/z

(ESI+) 383.5 ([M + Na]+, 100%); HRMS (ESI+) found 383.2211, expect 383.2198 for

C22H32O4Na.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S31

Methyl (E)-4,4-dimethyl-2-(3-oxobutyl)-7-phenylhept-6-enoate – S15

As described in general procedure B, reaction of methyl (E)-4,4-dimethyl-2-(2-(2-methyl-1,3-

dioxolan-2-yl)ethyl)-7-phenylhept-6-enoate (0.21 g, 0.58 mmol, 1 equiv.) and p-

toluenesulfonic acid monohydrate (0.22 g, 1.17 mmol, 2 equiv.) in acetone (10 mL), after

work-up and purification yielded S15 as a pale yellow oil (0.15 g, 83%); υmax / cm-1

2958,

1729, 1714, 1465, 1365, 1186, 1156; δH (500 MHz, CDCl3) 0.89 (3H, s, J 4.4, CH3), 0.90

(3H, s, J 4.4, CH3), 1.31 (1H, dd, J 14.2, 2.5, 1H from CH2), 1.78 (2H, q, J 7.6, CH2), 1.86

(1H, dd, J 14.2, 9.8, 1H from CH2), 2.08 - 2.12 (5H, m, CH2 + CH3), 2.41 (2H, q, J 7.4, CH2),

2.46 - 2.53 (1H, m, CH), 3.67 (3H, s, CO2CH3), 6.17 - 6.25 (1H, m, CH=CHPh), 6.38 (1H, d,

J 15.8, CH=CHPh), 7.20 (1H, tt, J 7.3, 1.3, ArCH), 7.30 (2H, t, J 7.3, ArCH), 7.36 (2H, d, J

7.6, ArCH); δC (125 MHz, CDCl3) 26.6 (CH3), 26.9 (CH3), 28.5 (CH2), 29.9 (CH3), 34.1

(quat. C), 40.5 (CH), 40.8 (CH2), 44.2 (CH2), 45.7 (CH2), 51.5 (CO2CH3), 125.9 (ArCH),

126.9 (ArCH), 127.0 (CH=CHPh), 128.4 (ArCH), 132.4 (CH=CHPh), 137.6 (ArC), 177.1

(CO2Me), 207.6 (CO); m/z (ESI+) 339.4 ([M + Na]+, 100%); HRMS (ESI+) found 339.1934,

expect 339.1936 for C20H28O3Na.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S32

rac-(3S,6S)-3-((E)-2,2-Dimethyl-5-phenylpent-4-en-1-yl)-6-methyl-6-(1-phenyl-2l5-propa-

1,2-dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1g

As described in general procedure D, reaction of methyl (E)-4,4-dimethyl-2-(3-oxobutyl)-7-

phenylhept-6-enoate (0.10 g, 0.32 mmol, 1 equiv.), (3-bromoprop-1-yn-1-yl)benzene (0.08 g,

0.41 mmol, 1.3 equiv.), SmI2 (11 mL, 1.11 mmol, 3.5 equiv.) and NiI2 (7 mg, 22.1 µmol, 2

mol % with respect to SmI2), after work-up and flash column chromatography (5%

EtOAc:hexane) yielded trans-1g as a yellow oil (combined yield for cis and trans isomers:

26%, for trans-1g: 13 mg, 13%); δH (500 MHz, CDCl3) 0.87 (3H, s, J 4.4, CH3), 0.88 (3H, s,

J 4.4, CH3), 1.17 (1H, dd, J 14.2, 5.4, 1H from CH2), 1.62 - 1.70 (4H, m, 1H from CH2 +

CH3), 1.83 - 1.91 (1H, m, 1H from CH2), 2.01 - 2.13 (2H, m, CH2), 2.15 - 2.22 (1H, m, 1H

from CH2), 2.25 (1H, dd, J 14.2, 4.1, 1H from CH2), 2.27 - 2.34 (1H, m, 1H from CH2), 2.51

- 2.58 (1H, m, CH), 5.14 (2H, s, C=CH2), 6.19 - 6.26 (1H, m, CH=CHPh), 6.32 (1H, d, J

15.8, CH=CHPh), 7.21 (1H, tt, J 7.3, 1.6, ArCH), 7.27 - 7.32 (3H, m, ArCH), 7.32 - 7.37

(4H, m, ArCH), 7.47 (2H, d, J 7.3, ArCH); δC (125 MHz, CDCl3) 26.1 (CH2), 26.9 (CH3),

26.9 (CH3), 28.8 (CH3), 32.4 (CH2), 34.3 (quat. C), 35.2 (CH), 42.9 (CH2), 45.9 (CH2), 78.7

(C=CH2), 82.7 (quat. C), 110.4 (C=C=CH2), 126.0 (ArCH), 126.9 (ArCH), 127.2 (ArCH),

127.5 (ArCH), 128.5 (ArCH), 128.9 (ArCH), 132.4 (CH2CH=CH and CH2CH=CH), 133.7

(ArC), 137.7 (ArC), 175.0 (CO), 207.3 (C=CH2); m/z (ESI+) 423.5 ([M + Na]+, 100%).

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S33

General Procedure G: Sonogashira reaction

5-Phenylpent-4-yn-1-ol – S164

An oven dried flask was degassed with N2 and loaded with THF (25 mL), DIPA (10 mL),

iodobenzene (2.70 mL, 24.1 mmol, 2 eq.) and 4-pentyn-1-ol (1.10 mL, 13.4 mmol, 1 equiv.).

PdCl2(PPh3)2 (173 mg, 0.25 mmol, 2 mol%) and CuI (30 mg, 0.16 mmol, 1 mol%) were

added to the mixture, which was heated under reflux for 18 hours. The reaction mixture was

filtered through celite, the residue washed and the filtrate concentrated in vacuo. The crude

product was purified by flash column chromatography (15% → 25% EtOAc:petroleum ether)

to give the named compound as a dark orange oil (1.55 g, 78%); δH (400 MHz, CDCl3) 1.82

(2H, quin, J 6.6, CH2), 2.50 (2H, t, J 7.1, CH2), 2.74 (1H, br. s, OH), 3.76 (2H, t, J 5.2, CH2),

7.19 - 7.30 (3H, m, ArH), 7.36 - 7.41 (2H, m, ArH); δC (100 MHz, CDCl3) 15.8 (CH2), 31.2

(CH2), 61.3 (CH2), 80.9 (C≡C), 89.3 (C≡C), 123.6 (ArC), 127.5 (ArCH), 128.1, (ArCH),

131.4, (ArCH).

(5-Iodopent-1-yn-1-yl)benzene – S174

As described in general procedure C, reaction of 5-phenylpent-4-yn-1-ol (0.15 g, 0.94 mmol,

1 equiv.), PPh3 (0.37 g, 1.43 mmol, 1.5 equiv.), imidazole (95.0 mg, 1.46 mmol, 1.5 equiv.)

and I2 (0.36 g, 1.42 mmol, 1.5 equiv.) after work-up and flash column chromatography

(hexane) yielded the named compound as a colourless oil (0.18 g, 72%); δH (400 MHz,

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S34

CDCl3) 2.11 (2H, quin, J 6.8, CH2), 2.57 (2H, t, J 6.7, CH2), 3.38 (2H, t, J 6.8, CH2), 7.27 -

7.33 (3H, m, ArH), 7.36 - 7.45 (2H, m, ArH); δC (100 MHz, CDCl3) 5.4 (CH2), 20.4 (CH2),

32.1 (CH2), 81.7 (C≡C), 87.8 (C≡C), 123.5 (ArC), 127.8 (ArCH), 128.2 (ArCH), 131.6

(ArCH).

Ethyl 2-(3-oxobutyl)-7-phenylhept-6-ynoate – S18

As described in general procedure A, treatment of ethyl 4-(2-methyl-1,3-dioxolan-2-

yl)butanoate (1.00 g, 4.94 mmol, 1 equiv.) in THF (2 mL) with 2.0 M LDA in hexane (3.50

mL, 5.50 mmol, 1.1 equiv.), followed by addition of (5-bromopent-1-yn-1-yl)benzene (1.32

g, 5.93 mmol, 1.2 equiv.) in HMPA (1.0 mL), after work-up gave the crude acetal protected

keto-ester, which was used without further purification. As described in general procedure B,

reaction of the crude ester with p-toluenesulfonic acid monohydrate (1.89 g, 9.89 mmol, 2

equiv.) in acetone (50 mL), after work-up and purification by column chromatography on

silica gel (petroleum ether → CH2Cl2:petroleum ether) gave the title compound (0.98 g, 66%

over 2 steps) as a colourless oil; νmax /cm-1

2937, 1716, 1598, 1490, 1366, 1257, 1153, 1096,

1069, 1025; δH (500 MHz, CDCl3) 1.27 (3H, t, J 7.1, CH2CH3), 1.57 - 1.70 (3H, m, 1H from

CH2 + CH2), 1.76 - 1.82 (1H, m, 1H from CH2), 1.85 (2H, q, J 7.8, CH2), 2.13 (3H, s, CH3),

2.37 - 2.49 (5H, m, CH + 1H from CH2 + 1H from CH2 + CH2), 4.16 (2H, q, J 7.1, CH2CH3),

7.26 - 7.31 (3H, m, ArH), 7.37 - 7.41 (2H, m, ArH); δC (125 MHz, CDCl3) 14.3 (CH3), 19.2

(CH2), 25.8 (CH2), 26.3 (CH2), 30.0 (CH3), 31.4 (CH2), 41.0 (CH2), 44.3 (CH), 60.3

(CH2CH3), 81.0 (PhC≡C), 89.4 (PhC≡C), 123.8 (ArC), 127.6 (ArCH), 128.2 (ArCH), 131.5

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S35

(ArCH), 175.5 (CO2Et), 207.9 (CO); m/z (ESI+) 301.3 ([M+H]+, 100%); HRMS (ESI+)

found 323.1613, expect 323.1623 for C19H24O3Na.

(3-Bromoprop-1-ynyl)dimethyl(phenyl)silane – S192

A solution of LDA was prepared by adding n-BuLi (1.54 M solution in hexane, 11.4 mL,

17.6 mmol, 1.1 equiv.) to diisopropylamine (2.40 g, 17.6 mmol, 1.1 equiv.) in Et2O (27 mL)

at -78 °C under N2 and stirring for 1 h. To this solution was added propargylic bromide (80%

solution in toluene, 1.78 mL, 16.0 mmol, 1 equiv.) and the reaction was stirred for 1 h before

the addition of chlorodimethyl(phenyl)silane (2.68 g, 16.0 mmol, 1 equiv.) and the resulting

reaction mixture allowed to warm to room temperature overnight. The reaction was quenched

by the addition of aqueous saturated NH4Cl (15 mL) and the aqueous layer extracted with

Et2O (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried

(Na2SO4) and concentrated in vacuo to yield the crude product. Purification by column

chromatography on silica gel eluting with 1:80 Et2O in pentane, gave the title compound

(3.70 g, 91%) as a yellow oil; δH (500 MHz, CDCl3) 0.31 (6H, s, Si(CH3)2Ph), 3.82 (2H, s,

CH2), 7.22-7.27 (3H, m, ArH), 7.48-7.50 (2H, m, ArH); δC (100 MHz, CDCl3) -1.3

(Si(CH3)2Ph), -1.1 (Si(CH3)2Ph), 14.5 (CH2), 90.3 (C≡CCH2), 101.6 (C≡CSi), 127.9 (ArCH),

133.6 (ArCH), 133.8 (ArCH), 136.2 (ArC).

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S36

(3R,6S)-6-(1-(Dimethyl(phenyl)silyl)-propa-1,2-dien-1-yl)-6-methyl-3-(5-phenylpent-4-yn-

1-yl)tetrahydro-2H-pyran-2-one – trans-1h

As described in general procedure D, reaction of methyl (E)-4,4-dimethyl-2-(3-oxobutyl)-7-

phenylhept-6-enoate (109 mg, 0.44 mmol, 1 equiv.), (3-bromoprop-1-

ynyl)dimethyl(phenyl)silane (112 mg, 0.57 mmol, 1.3 equiv.), SmI2 (13.0 mL, 1.33 mmol, 3

equiv.) and NiI2 (10.0 mg, 0.03 mmol, 2 mol % with respect to SmI2), after work-up and flash

column chromatography (petroleum ether → 5% EtOAc:petroleum ether) yielded trans-1h as

a colourless oil (combined yield for cis and trans isomers: 41%, for trans-1h: 73 mg, 21%);

νmax /cm-1

2954, 1927, 1731, 1489, 1428, 1249, 1098; δH (500 MHz, CDCl3) 0.35 - 0.38 (3H,

s, SiCH3), 0.45 - 0.49 (3H, s, SiCH3), 1.33 (3H, s, CH3), 1.35 - 1.49 (4H, m, 1H from CH2 +

1H from CH2 + CH2), 1.58 - 1.64 (1H, m, 1H from CH2), 1.70 - 1.83 (4H, m, CH2 + CH2),

1.89 (1H, ddd, J 13.7, 7.9, 5.5, 1H from CH2), 2.27 (2H, td, J 7.0, 2.4, CH), 4.53 (2H, s,

C=CH2), 7.18 - 7.33 (8H, m, ArH), 7.47 - 7.51 (2H, m, ArH); δC (125 MHz, CDCl3) -1.9

(SiCH3), -1.5 (SiCH3), 19.4 (CH), 22.8 (CH2), 26.1 (CH2), 29.6 (CH3), 30.7 (CH2), 33.3

(CH2), 38.3 (CH2), 72.3 (C=C=CH2), 80.9 (C≡CPh), 84.8 (quat. C), 89.7 (C≡CPh), 102.7

(C=C=CH2), 127.5 (ArCH), 127.8 (ArCH), 128.2 (ArCH), 129.2 (ArCH), 131.5 (ArCH),

131.9 (ArC), 134.1 (ArCH), 137.8 (ArC), 173.6 (CO), 207.9 (C=C=CH2); m/z (ESI+) 429.0

([M+H]+, 100%); HRMS (ESI+) found 451.2048, expect 451.2069 for C28H32O2SiNa.

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S37

6-Allyl-6-methyltetrahydro-2H-pyran-2-one - S205

As described in general procedure D, reaction of methyl 5-oxohexanoate (300 mg, 1.90

mmol, 1 equiv.), allyl bromide (252 mg, 2.09 mmol, 1.1 equiv.), SmI2 (76.0 mL, 7.59 mmol,

3 equiv.) and NiI2 (48.0 mg, 0.15 mmol, 2 mol % with respect to SmI2), after work-up and

flash column chromatography (petroleum ether → 10% EtOAc:petroleum ether) yielded S20

as a colourless oil (245 mg, 84%); δH (400 MHz, CDCl3) 1.37 (3H, s, CH3), 1.63 - 1.71 (1H,

m, 1H from CH2), 1.77 - 1.93 (3H, m, 1H from CH2 + CH2), 2.40 - 2.58 (4H, m, CH2 + CH2),

5.10 - 5.19 (2H, m, CH=CH2), 5.80 (1H, ddt, J 14.5, 10.2, 7.3, CH=CH2); δC (100 MHz,

CDCl3) 16.5 (CH2), 26.3 (CH3), 29.3 (CH2), 31.4 (CH2), 46.1 (CH2CH=CH2), 83.6 (quat. C),

119.4 (CH=CH2), 132.3 (CH=CH2), 171.2 (CO).

6-Cinnamyl-6-methyltetrahydro-2H-pyran-2-one – S215

As described in general procedure F, methyl 4,4-dimethylhept-6-enoate 6-allyl-6-

methyltetrahydro-2H-pyran-2-one (500 mg, 3.57 mmol, 1 equiv.), trans-stilbene (1.93 g, 10.7

mmol, 3 equiv.) and Hoveyda–Grubbs second generation catalyst (52.0 mg, 82.0 µmol, 2.3

mol%) in CH2Cl2 (10 mL) overnight at reflux with subsequent work-up and purification by

flash column chromatography (petroleum ether → 2% EtOAc:petroleum ether) yielded the

named compound as a yellow oil (300 mg, 40%); δH (400 MHz, CDCl3) 1.34 (3H, s, CH3),

1.59 - 1.67 (2H, m, CH2), 1.73 - 1.87 (2H, m, CH2), 2.33 - 2.47 (2H, m, CH2), 2.50 (2H, dd, J

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SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S38

7.4, 1.1, CH2CH=CHAr), 6.12 (1H, dt, J 15.7, 7.5, PhCH=CH), 6.39 (1H, d, J 15.7,

PhCH=CH), 7.12 - 7.31 (5H, m, ArH); δC (100 MHz, CDCl3) 16.5 (CH2), 26.4 (CH3), 29.3

(CH2), 31.6 (CH2), 45.4 (CH2), 84.0 (quat. C), 123.8 (PhCH=CH), 126.1 (ArCH), 127.4

(ArCH), 128.5 (ArCH), 134.2 (PhCH=CH), 136.9 (ArC), 171.2 (CO).

(E)-5-Phenylpent-4-en-1-ol – S226

To a solution of LiAlH4 (1.04 g, 27.3 mmol, 3 equiv.) in THF (16 mL) was added 5-

phenylpent-4-yn-1-ol (1.46 g, 9.11 mmol, 1 equiv.) dropwise at 0 °C. The reaction mixture

was stirred at 60 °C over night. Once complete and cooled to 0 °C, the reaction was diluted

with ether and carefully quenched with H2O. After the addition of Rochelle’s salt, the layers

were separated and the aqueous layer extracted with EtOAc (3 × 20 mL). The combined

organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in

vacuo. The compound was purified using flash column chromatography (petroleum ether →

5% → 10% → 20% EtOAc:petroleum ether), yielding the named compound as an orange oil

(1.33 g, 89%); δH (400 MHz, CDCl3) 1.73 – 1.82 (2H, m, CH2), 2.07 (1H, s, OH), 2.29 – 2.37

(2H, m, CH2), 3.71 (2H, t, J 6.4, CH2OH), 6.26 (1H, dt, J 15.7, 6.9, CH2CH=CH), 6.45 (1H,

d, J 15.9, CH2CH=CH), 7.21 – 7.26 (1H, m, ArH), 7.28 – 7.42 (4H, m, ArH); δC (100 MHz,

CDCl3) 29.3 (CH2), 32.1 (CH2), 62.2 (CH2), 125.8 (ArCH), 126.9 (ArCH), 128.4 (ArCH),

130.0 (CH=CHPh), 130.2 (CH=CHPh), 137.5 (ArC).

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S39

(E)-(5-Iodopent-1-en-1-yl)benzene - S237

As described in general procedure C, reaction of (E)-5-phenylpent-4-en-1-ol (1.16 g, 7.16

mmol, 1 equiv.), PPh3 (2.82 g, 16.8 mmol, 1.5 equiv.), imidazole (0.73 g, 16.8 mmol, 1.5

equiv.) and I2 (2.73 g, 16.8 mmol, 1.5 equiv.), after work-up and flash column

chromatography (hexane) yielded the title compound as a colourless oil (1.65 g, 85%); δH

(400 MHz, CDCl3) 1.93 (2H, quin, J 7.0, CH2), 2.27 (2H, qd, J 7.1, 1.4, CH2I), 3.16 (2H, t, J

6.9, CH2CH=CH), 6.08 (1H, dt, J 15.8, 7.0, CH2CH=CH), 6.39 (1H, d, J 15.8, CH2CH=CH),

7.14 (1H, tt, J 6.5, 1.5, ArH), 7.20 - 7.30 (4H, m, ArH); δC (100 MHz, CDCl3) 6.3 (CH2), 32.8

(CH2), 33.5 (CH2), 126.0 (ArCH), 127.1 (ArCH), 128.3 (ArCH), 128.5 (CH=CHPh), 131.3

(CH=CHPh), 137.4 (ArC).

(3R,6S)-6-Cinnamyl-6-methyl-3-((E)-5-phenylpent-4-en-1-yl)tetrahydro-2H-pyran-2-one –

trans-1i

As described in general procedure A, alkylation of (S)-6-cinnamyl-6-methyltetrahydro-2H-

pyran-2-one (250 mg, 1.08 mmol, 1 equiv.) using LDA (1 M, 1.22 mL, 1.20 mmol, 1.1

equiv.), then (E)-(5-iodopent-1-en-1-yl)benzene (887 mg, 3.25 mmol, 2.7 equiv.) in HMPA

(0.5 mL), after work-up and purification yielded trans-1i as a colourless oil (197 mg, 49%);

νmax /cm-1

2975, 2944, 1721, 1494, 449, 1380, 1360, 1298, 1199, 1110; δH (400 MHz, CDCl3)

1.41 - 1.45 (3H, s, CH3), 1.54 - 1.79 (5H, m, 1H from CH2 + CH2 + CH2), 1.85 - 2.04 (3H, m,

Page 40: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S40

1H from CH2 + CH2), 2.24 (2H, q, J 7.1, CH2), 2.40 - 2.48 (1H, m, CH), 2.50 - 2.62 (2H, m,

CCH2CH=CH), 6.13 - 6.25 (2H, m, 2 × PhCH=CH), 6.36 - 6.50 (2H, m, 2 × PhCH=CH),

7.17 - 7.26 (2H, m, ArH), 7.27 - 7.39 (8H, m, ArH); δC (100 MHz, CDCl3) 22.3 (CH2), 26.7

(CH2), 27.5 (CH3), 31.0 (CH2), 31.4 (CH2), 32.9 (CH2), 39.5 (CH), 44.6 (CCH2CH=CH),

83.8 (quat. C), 123.9 (PhCH=CH), 125.9 (ArCH), 126.2 (ArCH), 126.9 (ArCH), 127.5

(ArCH), 128.5 (ArCH), 128.6 (ArCH), 130.2 (PhCH=CH + PhCH=CH), 134.2 (PhCH=CH),

137.0 (ArC), 137.7 (ArC), 174.2 (CO); m/z (ESI+) 375.4 ([M+H]+, 100%); HRMS (ESI+)

found 397.2128, expect 397.2144 for C26H30O2Na.

Page 41: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S41

Crystal data and Structure Refinements

Figure S1 Crystal Structure of 2b (CCDC 1009956)

Table S1 Crystal data and structure refinement for 2b (CCDC 1009956)

Empirical formula C26H34O2

Formula weight 378.53

Temperature/K 566(2)

Crystal system orthorhombic

Space group Pca21

a/Å 13.7848(12)

b/Å 12.024(2)

c/Å 12.7279(13)

α/° 90

β/° 90

γ/° 90

Volume/Å3 2109.7(5)

Z 4

ρcalcmg/mm3 1.192

μ/mm-1

0.073

F(000) 824.0

2Θ range for data collection 6.402 to 50.052°

Index ranges -9 ≤ h ≤ 16, -14 ≤ k ≤ 5, -15 ≤ l ≤ 14

Page 42: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S42

Reflections collected 4485

Independent reflections 3103[R(int) = 0.0732]

Data/restraints/parameters 3103/1/257

Goodness-of-fit on F2 1.043

Final R indexes [I>=2σ (I)] R1 = 0.0906, wR2 = 0.1778

Final R indexes [all data] R1 = 0.1502, wR2 = 0.2192

Largest diff. peak/hole / e Å-3

0.25/-0.25

Page 43: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S43

Figure S2 Crystal Structure of 2d (CCDC 1012766)

Table S2 Crystal data and structure refinement for 2d (CCDC 1012766)

Empirical formula C26 H33 Br O2

Formula weight 457.43

Temperature 100(2) K

Wavelength 1.54178 Å

Crystal system Triclinic

Space group P-1

Unit cell dimensions a = 11.0845(3) Å

b = 12.9326(3) Å

c = 15.6251(4) Å

Volume 2210.80(10) Å3

Z 4

Density (calculated) 1.374 Mg/m3

Absorption coefficient 2.672 mm-1

F(000) 960

Crystal size 0.19 x 0.15 x 0.07 mm3

Theta range for data collection 3.43 to 72.15°.

Index ranges -13<=h<=12, -15<=k<=15, -19<=l<=19

Page 44: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S44

Reflections collected 19984

Independent reflections 8306 [R(int) = 0.0292]

Completeness to theta = 67.00° 96.3 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.8350 and 0.712437

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 8306 / 0 / 529

Goodness-of-fit on F2 1.046

Final R indices [I>2sigma(I)] R1 = 0.0329, wR2 = 0.0829

R indices (all data) R1 = 0.0368, wR2 = 0.0855

Largest diff. peak and hole 0.512 and -0.551 e.Å-3

Page 45: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S45

References

1 M. Szostak, M. Spain and D. J. Procter, J. Org. Chem., 2012, 77, 3049.

2 D. Parmar, H. Matsubara, K. Price, M. Spain and D. J. Procter, J. Am. Chem. Soc., 2012,

134, 12751.

3 N. Nazef, R. D. M. Davies and M. F. Greaney, Org. Lett., 2012, 14, 3720.

4 D. M. Barber, H. J. Sanganee and D. J. Dixon, Org. Lett., 2012, 14, 5290.

5 D. Parmar, K. Price, M. Spain, H. Matsubara, P. Bradley, D. J. Procter, J. Am. Chem. Soc.,

2011, 133, 2418.

6 R. Matsubara and T. F. Jamison, J. Am. Chem. Soc., 2010, 132, 6880.

7 A. Han, T. Spataru, J. Hartung, G. Li, and J. R. Norton, J. Org. Chem., 2014, 79, 1938.

Page 46: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

1H and

13C NMR spectra

Ethyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)hept-6-enoate – S2

2013-08-05-DJP-33.010.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-25-DJP-46.020.esp

192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 47: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S47

Ethyl 2-(3-oxobutyl)hept-6-enoate – S3

2013-11-27-DJP-50.010.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-11-27-DJP-50.013.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 48: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S48

(3R,6S)-6-Methyl-3-(pent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-yl)tetrahydro-2H-pyran-

2-one – trans-1a

2014-06-19-djp-40.020.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-22-djp-55.010.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 49: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S49

(3S,6S)-6-Methyl-3-(pent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-yl)tetrahydro-2H-pyran-

2-one – cis-1a

2014-06-13-djp-19.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-16-djp-5.010.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 50: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S50

(4S,4aS,5S,6S,7R,9aS)-4,5,7-Trimethyl-6-phenyldecahydro-4aH-benzo[7]annulene-4a,7-

diol - 2a

2013-02-05-Administrator-10.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-02-05-Administrator-10.011.001.1r.esp

160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 51: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S51

(1S,2R,3R,4S,5R)-1,3-Dimethyl-5-(pent-4-en-1-yl)-2-phenylcycloheptane-1,4-diol -3a

2013-02-05-djp-49.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-21-djp-55.010.001.1r.esp

144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

125 MHz, CDCl3

500 MHz, CDCl3

Page 52: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S52

(E)-Ethyl 2-(3-oxobutyl)-7-phenylhept-6-enoate – S5

2013-05-24-djp-41.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-05-24-djp-41.013.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 53: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S53

(3R,6S)-6-Methyl-3-((E)-5-phenylpent-4-en-1-yl)-6-(1-phenylpropa-1,2-dien-1-

yl)tetrahydro-2H-pyran-2-one – trans-1b

2013-07-18-djp-50.010.001.1r.esp

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-08-21-djp-48.010.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 54: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S54

(1S,2R,3R,4S,5R)-1,3-Dimethyl-2-phenyl-5-((E)-5-phenylpent-4-en-1-yl)cycloheptane-1,4-

diol – 4b

2013-08-21-djp-50.011.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-08-21-djp-50.010.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 55: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S55

(4R,4aR,5S,6S,7R,9aS)-4-Benzyl-5,7-dimethyl-6-phenyldecahydro-1H-benzo[7]annulene-

4a,7-diol – 2b

2013-09-11-djp-40.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2013-09-13-Administrator-58.011.001.1r.esp

152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 56: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S56

(4S,4aS,5R,6R,7S,9aR)-7-Methyl-5-(methyl-d)-6-phenyl-4-((S)-phenylmethyl-d)decahydro-

4aH-benzo[7]annulene-5,6-d2-4a,7-diol-d2 – 2b-D4

2014-06-19-djp-60.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-21-djp-56.010.001.1r.esp

144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

125 MHz, CDCl3

Page 57: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S57

Ethyl (E)-2-(3-oxobutyl)-7-(4-(trifluoromethyl)phenyl)hept-6-enoate – S6

2014-03-13-djp-27.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5

Chemical Shift (ppm)

2014-06-05-staff-5.010.001.1r.esp

208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 58: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S58

(3R,6S)-6-Methyl-6-(1-phenyl-propa-1,2-dien-1-yl)-3-((E)-5-(4-

(trifluoromethyl)phenyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-one – trans-1c

2014-01-28-staff-10.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-03-20-staff-28.012.001.1r.esp

208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 59: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S59

(4S,4aS,5R,6R,7S,9aR)-5,7-Dimethyl-6-phenyl-4-(4-(trifluoromethyl)benzyl)decahydro-

4aH-benzo[7]annulene-4a,7-diol – 2c

2014-06-16-djp-55.020.001.1r.esp

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-16-djp-55.021.001.1r.esp

168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 60: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S60

Ethyl (E)-7-(4-bromophenyl)-2-(3-oxobutyl)hept-6-enoate – S7

400 MHz, CDCl3

100 MHz, CDCl3

Page 61: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S61

rac-(3R,6S)-3-((E)-5-(4-Bromophenyl)pent-4-en-1-yl)-6-methyl-6-(1-phenyl-2l5-propa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1d

2014-07-08-DJP-6.010.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-07-08-djp-6.011.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

125 MHz, CDCl3

500 MHz, CDCl3

Page 62: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S62

(4S,4aS,5R,6R,7S,9aR)-4-(4-Bromobenzyl)-5,7-dimethyl-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2d

2014-03-10-djp-20.020.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-03-10-DJP-20.021.esp

152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 63: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S63

Ethyl (E)-2-(3-oxobutyl)-7-(p-tolyl)hept-6-enoate – S8

2014-07-02-djp-6.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-07-02-djp-6.011.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

125 MHz, CDCl3

500 MHz, CDCl3

Page 64: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S64

rac-(3R,6S)-6-Methyl-6-(1-phenyl-propa-1,2-dien-1-yl)-3-((E)-5-(p-tolyl)pent-4-en-1-

yl)tetrahydro-2H-pyran-2-one – trans-1e

2014-05-01-DJP-14.010.esp

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-07-04-djp-34.011.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

400 MHz, CDCl3

125 MHz, CDCl3

Page 65: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S65

(4S,4aS,5R,6R,7S,9aR)-5,7-Dimethyl-4-(4-methylbenzyl)-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2e

2014-06-19-DJP-42.010.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-21-djp-54_2.010.001.1r.esp

144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

125 MHz, CDCl3

Page 66: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S66

Ethyl (E)-7-(2-chlorophenyl)-2-(3-oxobutyl)hept-6-enoate – S9

2014-07-02-djp-7.010.001.1r.esp

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-07-04-djp-37.010.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 67: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S67

rac-(3R,6S)-3-((E)-5-(2-Chlorophenyl)pent-4-en-1-yl)-6-methyl-6-(1-phenyl-propa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1f

2014-03-20-staff-27.010.001.1r.esp

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-03-20-staff-27.012.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

125 MHz, CDCl3

500 MHz, CDCl3

Page 68: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S68

rac-(4S,4aS,5R,6R,7S,9aR)-4-(2-Chlorobenzyl)-5,7-dimethyl-6-phenyldecahydro-4aH-

benzo[7]annulene-4a,7-diol – 2f

2014-06-25-djp-48.014.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-25-djp-48.011.esp

160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 69: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S69

ethyl (E)-4,4-dimethylhepta-2,6-dienoate – S10

2014-05-05-djp-18.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-05-05-djp-18.011.001.1r.esp

200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 70: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S70

methyl (E)-4,4-dimethyl-7-phenylhept-6-enoate – S12

2014-06-25-djp-47.010.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-25-djp-47.011.esp

192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

400 MHz, CDCl3

100 MHz, CDCl3

Page 71: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S71

ethyl (E)-4,4-dimethyl-2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-7-phenylhept-6-enoate – S14

2014-05-30-djp-14.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-05-30-djp-14.011.001.1r.esp

184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 72: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S72

methyl (E)-4,4-dimethyl-2-(3-oxobutyl)-7-phenylhept-6-enoate – S15

2014-05-31-djp-17.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-05-31-djp-17.011.001.1r.esp

220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 73: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S73

(3S,6S)-3-((E)-2,2-dimethyl-5-phenylpent-4-en-1-yl)-6-methyl-6-(1-phenyl-2l5-propa-1,2-

dien-1-yl)tetrahydro-2H-pyran-2-one – trans-1g

2014-06-08-djp-40.010.001.1r.esp

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

2014-06-25-staff-50.012.esp

216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8

Chemical Shift (ppm)

500 MHz, CDCl3

125 MHz, CDCl3

Page 74: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S74

Ethyl 2-(3-oxobutyl)-7-phenylhept-6-ynoate – S18

100 MHz, CDCl3

400 MHz, CDCl3

Page 75: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S75

(3R,6S)-6-(1-(Dimethyl(phenyl)silyl)--propa-1,2-dien-1-yl)-6-methyl-3-(5-phenylpent-4-yn-

1-yl)tetrahydro-2H-pyran-2-one trans-1h

400 MHz, CDCl3

100 MHz, CDCl3

Page 76: SmI H O-Mediated 5-exo/6-exo Lactone Radical Cyclisation Cascades · SmI 2–H 2 O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al. S2 General Methods 1H-NMR

SmI2–H2O-mediated 5-exo/6-exo lactone radical cyclisation cascades Yalavac et al.

S76

(3R,6S)-6-Cinnamyl-6-methyl-3-(5-phenylpent-4-en-1-yl)tetrahydro-2H-pyran-2-one -

trans-1i

400 MHz, CDCl3

100 MHz, CDCl3